Clinicopathologic Conference Case 40-2007 William J. Triggs, M.D. Assoc. Professor of Neurology, University of Florida, Gainesville Didier Cros, M.D. Neurology, Massachusetts General Hospital

A 38-year-old man with weakness in the handsDifferential DiagnosisWilliam J. Triggs, M.D.

Presentation of Case 38-year-old man with hand weakness Asymmetric hand weakness R>L Variably progressive - some improvement Arm and leg weakness months later No convincing sensory involvement

Rheumatoid arthritis in remission X years No relevant family history

Case Presentation, contd Clinical Examination Weakness Normal sensation Absent reflexes No spasticity

No bulbar involvement

Case Presentation, contd Weakness Prominent in hands Within nerve distributions Wrist/finger extensor muscles (radial)

Mild elbow flexion, ankle dorsiflex (peroneal) Asymmetric weakness Right worse than left

Distal worse than proximal

Atrophy? No fasiculations

Case Presentation, contd Clinical Neurophysiological Examination Diffuse motor neuron disease No evidence of motor conduction block Empiric treatment for Motor neuron disease

Case Presentation, contd Negative laboratory evaluation Anti-GM1 antibody (which lab?) SPEP

Genetic testing HNPP Kennedys syndrome SMA

Metals (lead) ?

Differential Diagnosis Summary of clinical picture Asymmetric weakness Normal sensation Absent tendon reflexes Not axonal polyneuropathy Not entrapment neuropathy Not muscle disease

Differential DiagnosisMotor Neuron Disease vs. Multifocal Motor Neuropathy

Motor Neuron Disease UMN and LMN signs = ALS Clinical UMN signs Spasticity, bulbar, hyperreflexia

Clinical LMN signs Weakness, atrophy, fasiculations

Electrophysiologic evidence Denervation on EMG Transcranial Magnetic stimulation

Motor Neuron Disease UMN and LMN signs = ALS (most common) MND and ALS used synonymously UMN signs only - Primary Lateral Sclerosis (PLS) Spasticity, bulbar, hyperreflexia

LMN signs only - Progressive Muscular Atrophy (PMA) Weakness, atrophy, fasiculations

CaveatClinical signs in MND may be elusive EMG may show unsuspected LMN involvement (denervation) in patients with clinical diagnosis PLS TMS may show unsuspected UMN involvement in patients with clinical diagnosis PMA Relative preservation of reflexes a probable UMN sign

Lower Motor Neuron Syndromes Spinal muscular atrophy Onset in childhood or adolescence Negative genetic testing

X-linked bulbospinal muscular atrophy Gynecomastia, facial myokymia, SNAPs abnl. Negative genetic testing

Progressive muscular atrophy Monomelic amyotrophy Not always monomelic but not all four limbs.

LMN disease vs. Multifocal Motor Neuropathy Atrophy Distribution of weakness - named nerves Fasiculations Reflexes

Multifocal Motor Neuropathy Aquired immune-mediated demyelinating neuropathy Slowly progressive weakness without sensory involvement.

Rare: lifetime prevalence 1 in 100,000 population, Mean age: 40 years Males: females = 3:1 Rarely fatal and Most patients remain active and functional TREATABLE!!!

Defining Multifocal Motor Neuropathy immunology treatment physiology

Immunology of Multifocal Motor Neuropathy Monoclonal gammopathy Most often MGUS Paraneoplastic Motor Neuron Syndromes Associated with demyelinating neuropathies

Anti-ganglioside antibodies IgM anti-GM1 ganglioside most prevalent Also asialo-GM1, GM2, GD1a antibodies

Anti-GM1 antibody High titers may define treatable syndrome Variable prevalence reported (30-80%) Patient population versus methodology ?

May be nonspecific (e.g. small % ALS) Absence does not exclude diagnosis

Treatment of Multifocal Motor Neuropathy Gold standard of this diagnosis Initial studies- plasma exchange/cytoxan IVIg now standard treatment Some patients require cytotoxic therapy Prednisone ineffective

Diagnostic therapeutic trial Convincing response diagnostic Treatment trial must be adequate Identifying improvement elusive Quantify strength, quantitate physiology Failed treatment trial not exclusive

Electrophysiology of Multifocal Motor Neuropathy Overlap between MND (PMA) and multifocal motor neuropathy Normal sensory nerve conductions Low amplitude motor nerve conductions Denervation on needle EMG

Motor conduction block multifocal motor neuropathy Focal reduction in CMAP area Without temporal dispersion of CMAP Outside usual entrapment sites Not accompanied by evidence of diffuse nerve demyelination Conduction velocities Distal latencies

Motor conduction block not specific Motor neuropathy (multifocal) Demyelinating neuropathies (e.g. CIDP) Entrapment neuropathies Vasculitis pseudoconduction block

Physiology of motor conduction block Demyelination in demyelinating neuropathy Focal nerve demyelination in multifocal motor neuropathy ? Why not diffuse demyelination ? Insufficient pathological evidence Demyelination versus other mechanisms Alteration in axonal excitability ? Alteration in axonal ionic conductance ?

Identifying motor conduction block Variable criteria for definition Number of nerves studied Axonal loss with disease progression Routine studies provide limited assessment Nerve root stimulation may be necessary Not all patients have conduction block (unclear if these patients are distinct)

Nerve Root Stimulation in Multifocal Motor Neuropathy

Ulnar wrist Ulnar elbow Nerve root

Definite Multifocal Motor Neuropathy Weakness without sensory loss in distribution 2 or more named nerves. Early diffuse weakness excludes diagnosis. Conduction block 2 or more nerves. Normal sensory conduction velocity in same segments showing motor block. Normal sensory conductions (at least 3). Absence of UMN signs.Olney et al. 2003

Probable Multifocal Motor Neuropathy Weakness without sensory loss in distribution 2 or more named nerves. Early diffuse weakness excludes diagnosis. Conduction block 1 nerve or probable conduction block in 2 or more nerves. Normal sensory conduction velocity in same segments showing motor block. Normal sensory conductions (at least 3). Absence of UMN signs.Olney et al. 2003

Problems with Diagnostic Criteria Root stimulation results not accepted Research criteria vs. treatment criteria Published criteria will miss treatable patients Clinical practice should err on the side of treatment ?

DiagnosisMultifocal Motor Neuropathy

Clinical Diagnosis Didier Cros, M.D.

Diagnostic Test Didier Cros, M.D. EMG Studies

Discussion of Management

Didier Cros, M.D.

Right Radial July 2003Motor NCS R Radi al - EIP

Amplitude / LatencyForearm 1

1.7 mV / 4.5 ms

Forearm

1

2 1

3

5ms 500V 100mA

Elbow2 1

3

Elb ow 2 5ms 500V 100mA 3 Sp.Gr 3 5ms 500V 100mA

0.8 mV / 8.0 ms

Spiral Groove

0.6 mV / 11.4 ms

Right Median July 2003Motor NCS R Medi an - APB2

Amplitude / Latency1

Wrist1

3

Wri st 1 5ms 2mV 100mA

2 3

3.8 mV / 4.5 ms

Elbow

Elb ow 2

5ms 2mV 100mA Root Stimul ation R Ge nera l Nerve - Ro ot Sti m (Elec )

2.6 mV / 8.9 ms

2 Col li sio n Roo tStim R General Nerve - Root Stim Root 1.1 Root Before Collision

11

3

2 12

2 13

3 5ms 2mV 1.2 5ms 3 2mV Root 1.1 1.3

Root After Collision

5ms 2mV 51mA 5ms 2mV1 3

1.4 mV / 17.9 ms

1.2 5ms 2mV 51mA1.4 5ms 2mV

Right Ulnar July 2003Motor NCS R Ulna r - ADM 1 3 2 1 2 1 2 1 3 3 3 Wri st 1

Amplitude / Latency 5.8 mV / 3.5 ms

Wrist Below Ulnar Gr. Above Ulnar Gr.

5ms 5mV 35mA 4 B.Ul nar Gr 2 5.1 mV / 8.5 ms 5ms 5mV 81mA A.Ul nar Gr 3

5.0 mV / 10.4 ms

5ms 5mV 81mA Axi ll a 4 4.5 mV / 12.2 ms Axilla Root Stimul ation R Ge 2 nera l Nerve - Ro ot Sti m (Elec ) 5ms 5mV 100mA 1 3 2 Erb 's Pt 5 1 3 Erbs Point 3.0 mV / 15.9 ms Root 1.1 5ms 5mV 100mA 2 5ms 5mV 1 3 1.2

Root

2.0 mV / 18.2 ms

2 11 2 3

5ms 5mV

3

1.3 5ms 5mV 1.4

Left Peroneal July 2003Motor NCS L Peroneal - EDB 2Amplitude / Latency

1Ankle

32 1

Ankl e 1 5ms 1mV 100mA3 Sc.Notch 21.4 mV / 15.3 ms 1.4 mV / 7.9 ms

Fibular Head

2 1 3

5ms 1mV 84mA

S1 31.4 mV / 16.5 ms

Popliteal Fossa

5ms 1mV 40mA

Discussion of Management

Didier Cros, M.D.

Left Ulnar February 2004Motor NCS L Uln ar - ADM 2 1 3 2 1 3 B.Ul nar Gr 2 2 1 5ms 5mV 100mA Wri st 1 5ms 5mV 68mA

Amplitude / Latency 6.1 mV / 3.0 ms

Wrist

Below Ulnar Gr.

5.0 mV / 7.4 ms

3 Above Ulnar Gr. A.Ul nar Gr 3 4.6 mV / 8.9 ms Root Stimul ation L General Nerve - Root Stim (El ec) 5ms 5mV 100mA2 1 3 1.2 5ms 5mV

Root1 2 2 3 4

2.8 mV / 17.3 ms

1.3 1 3 5ms 5mV 5

Right Median February 2004Motor NCS R Medi an - APB

Amplitude / Latency1

Wrist

3 2 1

Wri st 1 5ms 2mV 79mA

5.9 mV / 4.1 ms

Elbow

3

Elb ow 2

3.7 mV / 9.0 ms

5ms 2mV 100mA Root Stimul ation R Ge nera l Nerve - Ro ot Sti m (Elec )

Root Before Collision

1 3 Col li sio n Roo tStim R General Nerve - Root Stim Root 1.1 5ms 2mV 2 1 2 1 3 4 2 3

2 13 4 54 5 1.2 2.1 1.3 5mV 58mA 5mV 1.4

Root After Collision

1

3 5ms 5ms 2mV 5ms

2.7 mV / 17.0 ms

5ms 5mV

Left Musculocutaneous - BicepsIVIGMotor NCS L Muscul ocutaneo us - Bicep s brachi iMotor NCS L Muscul ocutaneo us - Bicep s-brachi i

Cyclophosphomide22

Root Stimul ation L General Nerve - Root Stim (El ec)

Root Stimul ation L Muscul ocutaneous - bi ceps 1 Site 1 1 3 Erbs 5ms 2mV 100mA

1

3

Site 1 11 3 1.3 5ms 2mV

5ms 2mV 100mA

Point1

2

Root Stimul ation L General Nerve - Root Stim (El ec)1 2 3 4 1.3 5ms 2mV

Root

3

1.3 5ms 2mV

1

2

314 2 2 3 3 44 5

55

July 2003Amplitude /

1.4

5ms 2mV 1.2 Root 1.1 5ms 2mV 5ms 2mV Latency

Feb. 20041

Feb. 20065

2 Amplitude / Latency2 3 1

3 4

Amplitude / Latency

Erbs Root

4.1 mV / 4.3 ms2.6 mV / 6.0 ms

2.1 mV / 4.1 ms0.8 mV / 5.6 ms

Root 1.1

5ms 10mV

9.5 mV / 4.5 msNo Root

Right Radial - EIPIVIGMotor NCS R Radi al - EIP 2Forearm 1

Cyclophosphomide

Motor NCS R Radi al - EIP

1 2

3 1 2 1 3 3

Forearm 1 5ms 1mV 100mA Elb ow 2 5ms 1mV 100mA Sp.Gr 3 5ms 1mV 100mA

1

3 2 1

5ms 1mV 100mA

Forearm Elbow Spiral Gr

3

Elb ow 2 5ms 1mV 100mA

2 1 3

Sp.Gr 3 5ms 1mV 100mA

July 2003Amplitude / Latency

Feb. 2006Amplitude / Latency

Forearm Elbow Spiral Gr

1.7 mV / 4.5 ms0.8 mV / 8.0 ms 0.6 mV / 11. 4ms

2.6 mV / 3.5 ms1.7 mV / 5.3 ms 1.3 mV / 7.8 ms

Right Median - APBIVIGMotor NCS R Medi an - APB

Motor NCS R Medi an - APB

Cyclophosphomide2

Motor NCS R Median - APB

22

Wrist

12

31 3

1Wri st 1 5ms 5mV 100mAElb ow 2 5ms 5mV 100mA

3 2 1 3

1Wri st 1 5ms 5mV 79mA

3Wrist 1 5ms 5mV 21mA 2

Elb ow 2

Elbow1

5ms 5mV 100mA Col li sio n Roo tStim R General Nerve - Root Stim

1

3

Col li sio n Roo tStim R General Nerve - Root Stim2 3 2.1

Elbow 2 Col li sion RootStim R General Nerve - Root Stim 5ms 5mV 91mA

22

Root

3 Root 1.1

1

1

3

Root 1.1

5ms 5mV 51mA

5ms 5mV 58mA

5ms 5mV 30mA 22 1.2 5ms 5mV 30mA

1

July 2003 1Wrist Elbow Root

2 3 5ms 5mV 51mA 3.1 2 3 5ms 5mV 51mA 2.1

1.2

Feb. 2004 21

34

5mV 51mA 1.5 Amplitude / 5ms Latency 3.5 1.43.2

Amplitude / Latency

5 1.5 2.4 2.5 1.4 2.3 1.2 2.2 1.3

Feb. 2006 1 3 1 3

Amplitude / Latency

5 1.5 1.4 1.3 4 4 5mV 30mA 5ms 5ms 5mV 30mA

3.8 mV / 4.5 ms2.6 mV / 8.9 ms 1.4 mV / 17.9ms

5ms 5mV 2.2

5.9 mV / 4.1 ms3.7 mV / 9.0 ms 2.7 mV / 17.0ms

7.9 mV / 4.0 ms7.2 mV / 8.5 ms 6.5 mV / 17.0 ms

5ms 5mV

The study of right radial conduction to the extensor Indicis proprius shows a low-amplitude compound response, a conduction block (53%) in the forearm, and dispersion of the proximal motor responses.

Shows a mild decrease in amplitude of the motor response not meeting the criteria for conduction block in the forearm (top box), a CMAP on root stimulation not meeting the criteria for conduction block (middle box), and a CMAP on root stimulation with collision eliminating the ulnar contribution to the thenar response, a low-amplitude motor response meeting the criteria for conduction block (63%) (bottom box). Sp Gr denotes spiral groove .

The initial conduction study of the right median nerve shows conduction block (left). There was partial improvement in the right median motor fibers during treatment with intravenous immune globulin alone (center), with an increase in distal amplitude but persistent proximal conduction block. After the addition of cyclophosphamide, all conduction variables returned to normal values, and the proximal conduction block resolved (right).

The monopolar needle electrode (cathode) is inserted perpendicular to the skin, at the C6C7 interspace, 1 cm lateral to the spinous process, and advanced through the paraspinal muscles to the vertebral lamina in the parasagittal plane. The anode position is varied on the midline 3 to 4 cm rostral, lateral, and caudal to the cathode to ensure maximal motor response. Surface recording electrodes are placed over the biceps, triceps, abductor pollicis brevis, and abductor digiti minimi muscles. Cervical-root stimulation is accompanied by stimulation of the ulnar nerve at the wrist (S1) to collide with the descending impulses elicited by cervical-root stimulation (S2) of the C8, T1 motor fibers destined for the ulnar nerve. This eliminates the ulnar contribution to the motor response recorded from the surface electrodes over the thenar eminence that is, pure median motor response. (Figure concept and data courtesy of Dr. Peter T.C. Siao, Neurology Service, Massachusetts General Hospital.)