A noninterventional study evaluating the effectiveness and safety of lacosamide added to monotherapy in patients with epilepsy with partial-onset seizures in daily clinical practice: The VITOBA study

Objective

Evidence for the efficacy and safety of adjunctive lacosamide in the treatment of partial-onset seizures (POS) was gained during placebo-controlled clinical trials in patients with treatment-resistant seizures who were taking one to three concomitant antiepileptic drugs (AEDs). The VITOBA study (NCT01098162) evaluated the effectiveness and tolerability of adjunctive lacosamide added to one baseline AED in real-world clinical practice.

Methods

We conducted a 6-month observational study at 112 sites across Germany. Adult patients (≥16 years) with POS received lacosamide adjunctive to only one baseline AED. Seizure frequency reduction at the end of the observation period was compared with a 3-month retrospective baseline period.

Results

Five hundred seventy-one patients received lacosamide at least once (Safety Set [SS]); 520 provided evaluable seizure records (Full Analysis Set [FAS]); and 499 took in-label dosages of lacosamide (up to 400 mg) and were evaluated for effectiveness (modified FAS). Median baseline seizure frequency was 2.0 per 28 days: 47.1% of patients (235/499, mFAS) took a concomitant sodium channel–blocking (SCB) AED; 38.1% (190/499) had only one lifetime AED; and 18.4% (92/499) were aged ≥65 years (mFAS). At the final visit, 72.5% (358/494) of patients showed a ≥50% reduction in seizure frequency from baseline, 63.8% (315/494) showed a ≥75% reduction, and 45.5% (225/494) were seizure-free. Seizure freedom rates were higher in patients aged ≥65 years (56.7%) compared with patients aged <65 years (43.1%), in patients with ≤5 years epilepsy duration (52.5%) versus >5 years duration (41.0%), and when added to first monotherapy (60.5%) rather than as a later therapy option. Treatment-emergent adverse events (TEAEs) were reported by 48.5% (277/571) of patients (SS), with a profile similar to that observed in pivotal trials; 466 of patients (81.6%, SS) continued lacosamide therapy after the trial.

Significance

These results suggest that lacosamide use, added to one concomitant AED, was effective at improving seizure control and was well tolerated in patients treated in routine clinical practice.

Epilepsia 2015

Type II focal cortical dysplasia: Ex vivo 7T magnetic resonance imaging abnormalities and histopathological comparisons

Objective

In the present report, the correlations between ex vivo high-resolution imaging and specific histological and ultrastructural patterns in type II focal cortical dysplasia (FCD) have been studied to explain the differences in the magnetic resonance imaging (MRI) detection of dysplasia and to contribute to the presurgical imaging evaluation of this pathology.

Methods

Surgical specimens from 13 patients with FCD IIa/b were submitted to 7T MRI scanning, and then analyzed histologically and ultrastructurally to compare the results with the MRI findings. Region of interest (ROI)-based measures on T2-weighted images (T2wi) were quantitatively evaluated in the lesion and in adjacent perilesional gray and white matter.

Results

Matched histological sections and 7T T2wi showed that the core of the lesion was characterized by patchy aggregates of abnormal cells and fiber disorganization related to inhomogeneity of intracortical signal intensity. The quantitative approach on T2wi can help to distinguish the lesions and perilesional areas even in a clinical MRI-negative case. The ultrastructural study showed that the strong signal hyperintensity in the white matter of FCD IIb was related to a dysmyelination process associated with severe fiber loss and abnormal cells. Less severe histopathological features were found in FCD IIa, thus reflecting their less evident MRI alterations.

Interpretation

We suggest that white matter abnormalities in type IIb FCD are due to defects of the myelination processes and maturation, impaired by the presence of balloon cells. To reveal the presence and the border of type II cortical dysplasia on MRI, a quantitative ROI-based analysis (coefficient of variation) is also proposed. 

Annals of Neurology  2015

Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses

Objective

Neuromyelitis optica (NMO) attacks often are severe, are difficult to treat, and leave residual deficits. Here, we analyzed the frequency, sequence, and efficacy of therapies used for NMO attacks.

Methods

A retrospective review was made of patient records to assess demographic/diagnostic data, attack characteristics, therapies, and the short-term remission status (complete remission [CR], partial remission [PR], no remission [NR]). Inclusion criteria were NMO according to Wingerchuk's 2006 criteria or aquaporin-4 antibody–positive NMO spectrum disorder (NMOSD). Remission status was analyzed with generalized estimating equations (GEEs), a patient-based statistical approach.

Results

A total of 871 attacks in 185 patients (142 NMO/43 NMOSD, 82% female) were analyzed. The 1,153 treatment courses comprised high-dose intravenous steroids (HD-S; n = 810), plasma exchange (PE; n = 192), immunoadsorption (IA; n = 38), other (n = 80), and unknown (n = 33) therapies. The first treatment course led to CR in 19.1%, PR in 64.5%, and NR in 16.4% of attacks. Second, third, fourth, and fifth treatment courses were given in 28.2%, 7.1%, 1.4%, and 0.5% of attacks, respectively. This escalation of attack therapy significantly improved outcome (p < 0.001, Bowker test). Remission rates were higher for isolated optic neuritis versus isolated myelitis (p < 0.001), and for unilateral versus bilateral optic neuritis (p = 0.020). Isolated myelitis responded better to PE/IA than to HD-S as first treatment course (p = 0.037). Predictors of CR in multivariate GEE analysis were age (odds ratio [OR] = 0.97, p = 0.011), presence of myelitis (OR = 0.38, p = 0.002), CR from previous attack (OR = 6.85, p < 0.001), and first-line PE/IA versus HD-S (OR = 4.38, p = 0.006).

Interpretation

Particularly myelitis and bilateral optic neuritis have poor remission rates. Escalation of attack therapy improves outcome. PE/IA may increase recovery in isolated myelitis. 

Annals of  Neurology 2015

Identifying Non–Duchenne Muscular Dystrophy–Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs A Review

Importance  Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients.

Objectives  To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings).

Evidence Review  Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015.

Findings  The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD.

Conclusions and Relevance  Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false-negative results are a possibility.

JAMA Neurology 2015

Whole-Exome Sequencing in Familial Parkinson Disease

Importance  Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

Objective  To identify genetic variants contributing to disease risk in familial PD.

Design, Setting, and Participants  A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

Main Outcomes and Measures  Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

Results  The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

Conclusions and Relevance  TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

JAMA Neurology 2015

Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community

Importance  The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain.

Objective  To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers.

Design, Setting, and Participants  A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated.

Main Outcomes and Measures  Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures.

Results  At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB− noncarriers). These associations were largely independent of APOE4.

Conclusions and Relevance  In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.

JAMA Neurology 2015

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

Background

Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.

Methods

We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18–50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.

Findings

We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per year (95% CI 0·17–0·37) in the estriol group versus 0·37 relapses per year (0·25–0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37–1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.

Interpretation

Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.

Lancet Neurology 2015

Reflex seizures, traits, and epilepsies: from physiology to pathology

Summary

Epileptic seizures are generally unpredictable and arise spontaneously. Patients often report non-specific triggers such as stress or sleep deprivation, but only rarely do seizures occur as a reflex event, in which they are objectively and consistently modulated, precipitated, or inhibited by external sensory stimuli or specific cognitive processes. The seizures triggered by such stimuli and processes in susceptible individuals can have different latencies. Once seizure-suppressing mechanisms fail and a critical mass (the so-called tipping point) of cortical activation is reached, reflex seizures stereotypically manifest with common motor features independent of the physiological network involved. The complexity of stimuli increases from simple sensory to complex cognitive-emotional with increasing age of onset. The topography of physiological networks involved follows the posterior-to-anterior trajectory of brain development, reflecting age-related changes in brain excitability. Reflex seizures and traits probably represent the extremes of a continuum, and understanding of their underlying mechanisms might help to elucidate the transition of normal physiological function to paroxysmal epileptic activity.

Lancet Neurology 2015

Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial

Summary

Background

Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE.

Methods

We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35.

Findings

Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference −10·3%, 95% CI −24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group.

Interpretation

The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment.

Lancet Neurology 2015

Chikungunya virus–associated encephalitis A cohort study on La Réunion Island, 2005–2009

Objective: To estimate the cumulative incidence rate (CIR) of Chikungunya virus (CHIKV)–associated CNS disease during the La Réunion outbreak, and assess the disease burden and patient outcome after 3 years.

Methods: CHIKV-associated CNS disease was characterized retrospectively in a cohort of patients with positive CHIKV reverse transcriptase PCR or anti-CHIKV immunoglobulin M antibodies in the CSF and fulfilling International Encephalitis Consortium criteria for encephalitis or encephalopathy. Neurologic sequelae were assessed after 3 years.

Results: Between September 2005 and June 2006, 57 patients were diagnosed with CHIKV-associated CNS disease, including 24 with CHIKV-associated encephalitis, the latter corresponding to a CIR of 8.6 per 100,000 persons. Patients with encephalitis were observed at both extremes of age categories. CIR per 100,000 persons were 187 and 37 in patients below 1 year and over 65 years, respectively, both far superior to those of cumulated causes of encephalitis in the United States in these age categories. The case-fatality rate of CHIKV-associated encephalitis was 16.6% and the proportion of children discharged with persistent disabilities estimated between 30% and 45%. Beyond the neonatal period, the clinical presentation and outcomes were less severe in infants than in adults.

Conclusions: In the context of a large outbreak, CHIKV is a significant cause of CNS disease. As with other etiologies, CHIKV-associated encephalitis case distribution by age follows a U-shaped parabolic curve.

Neurology 2015

Remote ischaemic conditioning—a new paradigm of self-protection in the brain

Remote ischaemic conditioning (RIC) triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuroprotection. RIC involves repetitive inflation and deflation of a blood pressure cuff on the limb, and is safe and feasible. The exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system seem to have critical roles. Early-phase clinical trials have already been conducted to test RIC in the prehospital setting in acute ischaemic stroke, and in subarachnoid haemorrhage for the prevention of delayed cerebral ischaemia. Furthermore, two small randomized clinical trials in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuroprotective activity. RIC represents a highly practical and translatable therapy for acute, subacute, and chronic neurological diseases with an ischaemic or inflammatory basis. In this Review, we consider the principles and mechanisms of RIC, evidence from preclinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury.

Nature Reviews Neurology 2015

Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia

Importance  To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or Alzheimer disease (AD) dementia, markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk.

Objective  To examine associations of impaired olfaction with incident MCI subtypes and progression from MCI subtypes to AD dementia.

Design, Setting, and Participants  Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging between 2004 and 2010 were clinically evaluated at baseline and every 15 months through 2014. Participants (N = 1630) were classified as having normal cognition, MCI (amnestic MCI [aMCI] and nonamnestic MCI [naMCI]), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function.

Main Outcomes and Measures  Mild cognitive impairment, AD dementia, and longitudinal change in cognitive performance measures.

Results  Of the 1630 participants who were cognitively normal at the time of the smell test, 33 died before follow-up and 167 were lost to follow-up. Among the 1430 cognitively normal participants included, the mean (SD) age was 79.5 (5.3) years, 49.4% were men, the mean duration of education was 14.3 years, and 25.4% were APOE ε4 carriers. Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in B-SIT score, and an increased risk of aMCI. Compared with the upper B-SIT quartile (quartile [Q] 4, best scores), hazard ratios (HRs) (95% CI) were 1.12 (0.65-1.92) for Q3 (P = .68); 1.95 (1.25-3.03) for Q2 (P = .003); and 2.18 (1.36-3.51) for Q1 (P = .001) (worst scores; P for trend <.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD dementia, with a significant dose-response with worsening B-SIT quartiles. Compared with Q4, HR (95% CI) estimates were 3.02 (1.06-8.57) for Q3 (P = .04); 3.63 (1.19-11.10) for Q2 (P = .02); and 5.20 (1.90-14.20) for Q1 (P = .001). After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10 [95% CI, 1.04-1.16]; P < .001) and improved the model concordance.

Conclusions and Relevance  Olfactory impairment is associated with incident aMCI and progression from aMCI to AD dementia. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress.

JAMA Neurology 2015

Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation

Importance  Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses.

Objectives  To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation.

Design, Setting, and Participants  Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012.

Main Outcomes and Measures  Correlation of regional and total brain scores with disease duration.

Results  Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus.

Conclusions and Relevance  Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials.

JAMA Neurology 2015