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JNNP Online First, published on January 27, 2015 as 10.1136/jnnp-2014-310287 PostScript
LETTER
Neuropsychological impairment in natalizumab-associated progressive multifocal leukoencephalopathy: implications for early diagnosis INTRODUCTION Immunocompromised patients and, recently, natalizumab (NAT)-treated patients with multiple sclerosis (MS) are at risk to develop the relatively rare but
potentially fatal opportunistic central nervous system infection progressive multifocal leukoencephalopathy (PML). As rapid immune reconstitution by removal of NAT appears to determine prognosis, early diagnosis is mandatory.1 Neuropsychological symptoms are common in early stages of disease,2 yet data on neuropsychological function in NAT-PML is lacking. Few studies in HIV-associated PML have demonstrated a reduction in attention/working memory, visuospatial abilities and motor speed.3 We compare the neuropsychological performance of patients with NAT-PML with patients with relapsing–remitting (RR) MS
during NAT therapy and patients with RR multiple sclerosis (RRMS) with relapse; we identify specific neuropsychological abnormalities that might support early NAT-PML diagnosis.
METHODS Our monocentric retrospective analysis of data obtained during routinely performed investigations was approved by the local ethics committee (No 4566-13). Epidemiological characteristics of patients with NAT-PML (n=8, definite diagnosis4) and controls (stable NAT-treated patients, n=9; patients with RRMS with preceding relapse, n=14) are given in table 1. The time
Table 1 Basic characteristics and neuropsychological scales Variable
NAT-PML (n=8)
NAT-treated RRMS (n=9)
RRMS with preceding relapse (n=14)
p Value PML vs NAT
p Value PML vs RRMS
Female Age (years) Age at MS diagnosis (years) Number of NAT infusions Duration NAT therapy (years) EDSS at initiation of NAT EDSS at neuropsychological testing Total ARR Number of previous MS therapies Previous use of mitoxantrone Anti-NAT antibodies Anti-JCV antibodies Patients treated with mirtazapine Patients treated with mefloquine Calculated premorbid IQ Years of education Steroid medication before neuropsychological testing Neuropsychological test Wechsler Memory Scale Subscales Digits backward Digits forward Shulman Clock Drawing Test Regensburger Word Fluency Test Subtests Semantic fluency test Change of categories Rey Auditory Verbal Learning Test 1. Repetition 5. Repetition Interference 6. Repetition 7. Repetition Recognition Wechsler Memory Scale Subscale: visual reproduction I (immediately) Wechsler memory scale Subscale: information and orientation questions Beck Depression Inventory II
6 (75%) 37.4 (SD 4.9) 25.7 (SD 6.3, n=7) 43.1 (SD 17.7) 3.6 (SD 1.4) 2.3 (SD 1, n=7) 4.6 (SD 1.1) 0 (IQR 0) 1.3 (SD 0.5, n=7) 1 (12.5%) 0 8 (100%) 6 (75%) 7 (87.5%) 70 (IQR 17.5) 13.8 (SD 3.2)
6 (66.7%) 41.9 (SD 9) 29.9 (SD 13.9) 32.6 (SD 19.8) 2.9 (SD 1.6) 3.3 (SD 0.9, n=6) 3.7 (SD 1.9) 0 (IQR 0.9) 1.3 (0.9, n=8) 2 (22.2%) 0 5 (55.6%) 2 (22.2%) 0 70 (IQR 25) 14.7 (SD 2.3)
11 (78.6%) 32.4 (SD 9.1) 22.7 (SD 9.1) NA NA NA 2.8 (SD 1.2, n=13) 1 (IQR 2) 0.8 (SD 0.9, n=12) 0 (0%) 0 2 (14.3%) 1 (7.1%) 0 70 (IQR 7.5) 15 (SD 1.9) 3000 mg (IQR 2250)
1* 0.03 † 0.18† 0.1† 0.2† 0.11† 0.22† 0.58† 0.87† 1* NA 0.08* 0.03*
JNNP Online First, published on January 27, 2015 as 10.1136/jnnp-2014-310287 PostScript
LETTER
Neuropsychological impairment in natalizumab-associated progressive multifocal leukoencephalopathy: implications for early diagnosis INTRODUCTION Immunocompromised patients and, recently, natalizumab (NAT)-treated patients with multiple sclerosis (MS) are at risk to develop the relatively rare but
potentially fatal opportunistic central nervous system infection progressive multifocal leukoencephalopathy (PML). As rapid immune reconstitution by removal of NAT appears to determine prognosis, early diagnosis is mandatory.1 Neuropsychological symptoms are common in early stages of disease,2 yet data on neuropsychological function in NAT-PML is lacking. Few studies in HIV-associated PML have demonstrated a reduction in attention/working memory, visuospatial abilities and motor speed.3 We compare the neuropsychological performance of patients with NAT-PML with patients with relapsing–remitting (RR) MS
during NAT therapy and patients with RR multiple sclerosis (RRMS) with relapse; we identify specific neuropsychological abnormalities that might support early NAT-PML diagnosis.
METHODS Our monocentric retrospective analysis of data obtained during routinely performed investigations was approved by the local ethics committee (No 4566-13). Epidemiological characteristics of patients with NAT-PML (n=8, definite diagnosis4) and controls (stable NAT-treated patients, n=9; patients with RRMS with preceding relapse, n=14) are given in table 1. The time
Table 1 Basic characteristics and neuropsychological scales Variable
NAT-PML (n=8)
NAT-treated RRMS (n=9)
RRMS with preceding relapse (n=14)
p Value PML vs NAT
p Value PML vs RRMS
Female Age (years) Age at MS diagnosis (years) Number of NAT infusions Duration NAT therapy (years) EDSS at initiation of NAT EDSS at neuropsychological testing Total ARR Number of previous MS therapies Previous use of mitoxantrone Anti-NAT antibodies Anti-JCV antibodies Patients treated with mirtazapine Patients treated with mefloquine Calculated premorbid IQ Years of education Steroid medication before neuropsychological testing Neuropsychological test Wechsler Memory Scale Subscales Digits backward Digits forward Shulman Clock Drawing Test Regensburger Word Fluency Test Subtests Semantic fluency test Change of categories Rey Auditory Verbal Learning Test 1. Repetition 5. Repetition Interference 6. Repetition 7. Repetition Recognition Wechsler Memory Scale Subscale: visual reproduction I (immediately) Wechsler memory scale Subscale: information and orientation questions Beck Depression Inventory II
6 (75%) 37.4 (SD 4.9) 25.7 (SD 6.3, n=7) 43.1 (SD 17.7) 3.6 (SD 1.4) 2.3 (SD 1, n=7) 4.6 (SD 1.1) 0 (IQR 0) 1.3 (SD 0.5, n=7) 1 (12.5%) 0 8 (100%) 6 (75%) 7 (87.5%) 70 (IQR 17.5) 13.8 (SD 3.2)
6 (66.7%) 41.9 (SD 9) 29.9 (SD 13.9) 32.6 (SD 19.8) 2.9 (SD 1.6) 3.3 (SD 0.9, n=6) 3.7 (SD 1.9) 0 (IQR 0.9) 1.3 (0.9, n=8) 2 (22.2%) 0 5 (55.6%) 2 (22.2%) 0 70 (IQR 25) 14.7 (SD 2.3)
11 (78.6%) 32.4 (SD 9.1) 22.7 (SD 9.1) NA NA NA 2.8 (SD 1.2, n=13) 1 (IQR 2) 0.8 (SD 0.9, n=12) 0 (0%) 0 2 (14.3%) 1 (7.1%) 0 70 (IQR 7.5) 15 (SD 1.9) 3000 mg (IQR 2250)
1* 0.03 † 0.18† 0.1† 0.2† 0.11† 0.22† 0.58† 0.87† 1* NA 0.08* 0.03*
