Electrophysiology & Leukodystrophies Shahriar Nafissi Department of Neurology Tehran University of Medical Sciences

Abbreviations EMG: electromyography NCS: nerve conduction studies VEP: visual evoked potential BAEP: brainstem auditory evoked potential SEP: somatosensory evoked potential MEP: motor evoked potential ALD: adrenoleukodystrophy MLD: Metachromatic leukodystrophy KD : Krabbe Disease PMD: Pelizieus-Merzbacher Disease

Overview Valuable in differentiating certain leukodystrophies from others Helpful in differentiating leukodystrophies from other demyelinating disorders Often reveals symmetric involvement of long spinal tracts and peripheral nerves, particularly after the first decade Serial longitudinal studies show gradual deterioration in neurophysiologic studies

Krabbe Disease (KD)

Nerve conduction studies Demyelinating SM polyneuropathy No conduction block NCS correlates with clinical severity and MRI abnormalities NCS, in combination with neuroimaging studies, appear to be the most sensitive laboratory measures to help assess the severity and the phenotypic classification of Krabbe 100% of early infantile cases (even pre-symptomatic) have NCS abnormalities 20-50% of late onset cases show NCS abnormalities A case with UMN and LMN involvement mimicing ALS; NCS showed demyelinating PN and sensory involvement A case of LOKD with onset of demyelinating PN 4 years before presentation of UMN findings

Serial Neurophysiological Studies in Late-Infantile Krabbe Disease

Evoked Potentials BAEP ▫abnormalities appear as early as 2 weeks after birth ▫First prolongation of IPL, then Loss of waves III and V ▫Early infantile symptomatic 100% abnormal ▫Early infantile pre-symptomatic 50% abnormal ▫All early infantile cases after 4 months had abnormal BAEP ▫Late onset: 40% abnormal VEP ▫Early infantile symptomatic 67% abnormal ▫Early infantile pre-symptomatic 0% abnormal ▫None of early infantile cases had abnormal VEP before 4 months ▫Late onset 0% abnormal

EEG in KD EEGs were abnormal in 65% of EIKD and 33% of LOKD children Abnormalities included ▫diffuse slowing ▫Seizure discharges ▫Frontal suppression ▫poor background with central spikes

Metachromatic Leukodystrophy (MLD)

MLD In the late onset cases, NCS is usually abnormal but NCS could be normal, especially in early stages The conduction velocities usually in the demyelinating but sometimes in axonal range Partial conduction block reported in few cases Few cases with peripheral neuropathy as the presenting feature have been reported, some resembling GBS or CIDP VEP usually normal in late onset MLD VEP In late infantile forms, normal in early stages, becomes delayed with progression

the involvement of peripheral nervous system from disease onset proved to be a sensitive prognostic marker predicting a severe progression The more severe the NCS changes, more severe the clinical phenotype Cases with a more benign course have normal NCS at presentation

Adrenoleukodystrophy (ALD) & Adrenomyeloneuropathy (AMN)

Evoked potentials BAEP usually normal in the first decade, later becomes abnormal after BS involvement VEP usually abnormal after extensive demyelinating lesions in the occipital white matter SEP and MEP become abnormal even later Even patients with a normal MRI may have an abnormal neurophysiologic pattern Sequence of abnormality: BAEP, VEP, SEP, MEP

ALD: slow wave bursts in the occipital region

Adrenomyeloneuropathy (AMN) neuropathy has mixed features of axonal degeneration and multifocal demyelination Some abnormality found in 82% More common in men than in women (87% v 67%); in legs than in arms (77% v 38%); in motor than in sensory conduction (80% v 39%); and in latency (distal and F wave) and velocity compared with amplitude (80% v 29%). Twenty six patients (19%) had at least one nerve variable value in the demyelinating range

Pelizaeus-Merzbacher Disease (PMD)

PNS involvement in PMD Null mutations in PLP gene are usually associated with polyneuropathy with milder CNS involvement Abnormal NCS is seen in both involved males and female carriers Axonal or Demyelinating polyneuropathy sometimes with non-uniform slowing In a series of 43 patients, 4 had neuropathy (2 axonal, 2 demyelinating)

Evoked Potentials BAEP ▫Increased IPL and absence of all waveforms except I or I-II ▫Can distinguish PMD from PM like disorders: 7/7 abnormal in PMD, 2/13 abnormal in PMLD MEP ▫Increased central motor conduction time ▫Absence of CMAP after cortical stimulation but present after cervical stimulation

PMD vs. PMLD