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LETTER
Clinical and paraclinical findings in natalizumab-associated infratentorial progressive multifocal leukoencephalopathy patients INTRODUCTION Natalizumab (NAT)-treated relapsing remitting multiple sclerosis (RRMS) patients have a marked progressive multifocal leukoencephalopathy (PML) risk, with an overall incidence of 3.4 per 1000 NAT treated patients (95%− CI 3.08 to 3.74).1 In HIV-positive PML patients a supratentorial manifestation occurred in 93.8%. An infratentorial PML manifestation is less frequent, occurring in 11–58.3% of the HIV-positive PML patients.2 3 Within the infratentorial brain structures, the pons is most commonly affected.2 Irie et al reported a infratentorial PML manifestation in one patient with renal failure. They found an overall survival of ≤4 months after onset of infratentorial PML symptoms.4 Up to now no clinical studies regarding NAT-PML with a predominant infratentorial manifestation have been published. Our study aimed to investigate differences in clinical data and disease course between NAT-PML patients with or without initial infratentorial involvement.
METHODS NAT-PML patients treated in two German university hospitals (Bochum n=21, Hannover n=3,) until 1 November 2013 were included in this retrospective study (ethic committees: Bochum 4566–13, Hannover: 2100−2013). Treatment of NAT-PML was standardised including plasma exchange, mirtazapine and mefloquine treatment. Patients were followed for 14.6±12.4 months (mean±SD), basic characteristics and clinical data were collected by medical records. Extended Disability Status Scale (EDSS) and Karnofsky Index (KI) were performed at onset, after the immune reconstitution inflammatory syndrome (IRIS), and after 6 months post-NAT-PML diagnosis, 1,5-Tesla MRI scans were obtained. Compared with our preceding work,5 we focused on the speciality of infratentorial PML manifestations and included a larger patient population. Statistical analysis was performed using SPSS 20 for windows. The incidence per 1000 patients for an initial infratentorial PML manifestation was J Neurol Neurosurg Psychiatry October 2014 Vol 85 No 10
calculated by extrapolating our data to the manufacturer-provided incidence rates.1
RESULTS Eight of 24 NAT-PML patients had an initial infratentorial manifestation on MRI. Of those, three were exclusively infratentorial (3/8), and 5 infratentorial and supratentorial (5/8) (see online supplementary figure 1). Within this patient population, pons and cerebellum were most commonly affected. The first clinical symptoms in infratentorial NAT-PML patients was most commonly a cerebellar dysfunction (6/8), followed by paresis (5/8), dysarthria (3/8) and sensory impairment (2/8). A cognitive deterioration (3/8) was reported only in those patients with additional supratentorial involvement early in PML. No differences were found in immunosuppressive pretreatment and duration from first PML symptoms to definite diagnosis of NAT-PML. A tendency towards a higher copy number of JCV in cerebrospinal fluid (CSF) in infratentorial NAT-PML patients and a significant longer duration of NAT treatment with more NAT infusions could be identified (table 1). We calculated incidence rates per 1000 patients of an initial infratentorial PML in dependence of NAT therapy duration. Patients treated less than 3 years with NAT had the lowest incidence of an initial infratentorial PML (13– 24 months: 0.22; 25–36 months: 0.26). Afterwards, incidence increased slightly (37–48 months: 0.40; 49–60 months 0.58) reaching its maximum after ≥5 years of therapy (>60 months: 2.08). In both groups, a worsening of EDSS (EDSS prior PML vs EDSS at diagnosis (mean±SD) 2.7±1.4 vs 4.6±2.0, p≤0.001) and KI (KI prior PML vs KI at diagnosis (mean±SD) 88.3±13.1 vs 60.6±19.8, p≤0.001) was observed. However, severity was different. Infratentorial PML patients were more affected at the beginning, demonstrated a pronounced deterioration during IRIS (difference between EDSS prior PML and EDSS post-IRIS (mean±SD): supratentorial −2.9±2.3 vs infratentorial −4.7±1.6, p≤0.05; difference between KI prior PML and KI post-IRIS (mean±SD): supratentorial 32±16.6 vs infratentorial 55±16, p≤0.01), and had worse functional recovery after 6 months (table 1). After stratification by EDSS (EDSS ≥7 vs
PostScript
LETTER
Clinical and paraclinical findings in natalizumab-associated infratentorial progressive multifocal leukoencephalopathy patients INTRODUCTION Natalizumab (NAT)-treated relapsing remitting multiple sclerosis (RRMS) patients have a marked progressive multifocal leukoencephalopathy (PML) risk, with an overall incidence of 3.4 per 1000 NAT treated patients (95%− CI 3.08 to 3.74).1 In HIV-positive PML patients a supratentorial manifestation occurred in 93.8%. An infratentorial PML manifestation is less frequent, occurring in 11–58.3% of the HIV-positive PML patients.2 3 Within the infratentorial brain structures, the pons is most commonly affected.2 Irie et al reported a infratentorial PML manifestation in one patient with renal failure. They found an overall survival of ≤4 months after onset of infratentorial PML symptoms.4 Up to now no clinical studies regarding NAT-PML with a predominant infratentorial manifestation have been published. Our study aimed to investigate differences in clinical data and disease course between NAT-PML patients with or without initial infratentorial involvement.
METHODS NAT-PML patients treated in two German university hospitals (Bochum n=21, Hannover n=3,) until 1 November 2013 were included in this retrospective study (ethic committees: Bochum 4566–13, Hannover: 2100−2013). Treatment of NAT-PML was standardised including plasma exchange, mirtazapine and mefloquine treatment. Patients were followed for 14.6±12.4 months (mean±SD), basic characteristics and clinical data were collected by medical records. Extended Disability Status Scale (EDSS) and Karnofsky Index (KI) were performed at onset, after the immune reconstitution inflammatory syndrome (IRIS), and after 6 months post-NAT-PML diagnosis, 1,5-Tesla MRI scans were obtained. Compared with our preceding work,5 we focused on the speciality of infratentorial PML manifestations and included a larger patient population. Statistical analysis was performed using SPSS 20 for windows. The incidence per 1000 patients for an initial infratentorial PML manifestation was J Neurol Neurosurg Psychiatry October 2014 Vol 85 No 10
calculated by extrapolating our data to the manufacturer-provided incidence rates.1
RESULTS Eight of 24 NAT-PML patients had an initial infratentorial manifestation on MRI. Of those, three were exclusively infratentorial (3/8), and 5 infratentorial and supratentorial (5/8) (see online supplementary figure 1). Within this patient population, pons and cerebellum were most commonly affected. The first clinical symptoms in infratentorial NAT-PML patients was most commonly a cerebellar dysfunction (6/8), followed by paresis (5/8), dysarthria (3/8) and sensory impairment (2/8). A cognitive deterioration (3/8) was reported only in those patients with additional supratentorial involvement early in PML. No differences were found in immunosuppressive pretreatment and duration from first PML symptoms to definite diagnosis of NAT-PML. A tendency towards a higher copy number of JCV in cerebrospinal fluid (CSF) in infratentorial NAT-PML patients and a significant longer duration of NAT treatment with more NAT infusions could be identified (table 1). We calculated incidence rates per 1000 patients of an initial infratentorial PML in dependence of NAT therapy duration. Patients treated less than 3 years with NAT had the lowest incidence of an initial infratentorial PML (13– 24 months: 0.22; 25–36 months: 0.26). Afterwards, incidence increased slightly (37–48 months: 0.40; 49–60 months 0.58) reaching its maximum after ≥5 years of therapy (>60 months: 2.08). In both groups, a worsening of EDSS (EDSS prior PML vs EDSS at diagnosis (mean±SD) 2.7±1.4 vs 4.6±2.0, p≤0.001) and KI (KI prior PML vs KI at diagnosis (mean±SD) 88.3±13.1 vs 60.6±19.8, p≤0.001) was observed. However, severity was different. Infratentorial PML patients were more affected at the beginning, demonstrated a pronounced deterioration during IRIS (difference between EDSS prior PML and EDSS post-IRIS (mean±SD): supratentorial −2.9±2.3 vs infratentorial −4.7±1.6, p≤0.05; difference between KI prior PML and KI post-IRIS (mean±SD): supratentorial 32±16.6 vs infratentorial 55±16, p≤0.01), and had worse functional recovery after 6 months (table 1). After stratification by EDSS (EDSS ≥7 vs
