Neurocognitive Trajectory of Boys Who Received a Hematopoietic Stem Cell Transplant at an Early Stage of Childhood Cerebral Adrenoleukodystrophy

Abstract

Importance  Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT.

Objectives  To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning.

Design, Setting, and Participants  Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity).

Main Outcomes and Measures  Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function.

Results  Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = –0.340; P = .008), perceptual reasoning (r = –0.419; P = .001), and processing speed (r = –0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment in at least 1 neurocognitive domain at the most recent evaluation.

Conclusions and Relevance  Boys with cALD who have greater than minimal cerebral disease detected on MRI scans at the time of an HSCT are at risk for severe, persistent neurocognitive deficits. These findings motivate further exploration of methods of detecting cerebral disease prior to development of lesions observable on MRI scans, an endeavor that may be facilitated by newborn screening for adrenoleukodystrophy. These findings may serve a benchmark role in evaluating the efficacy of novel interventions for cALD.

JAMA Neurology 2017

HISTORY OF NEUROLOGY- Progressive atrophy of the globus pallidus (primary atrophy of the pallidal system). A system disease of the paralysis agitans type, characterized by atrophy of the motor cells of the corpus striatum. A contribution to the function of the corpus striatum. By J. Ramsay Hunt MD, New York. Brain 1917; 40: 58–148

Is it the ‘shaking palsy’, ‘paralysis agitans’ or ‘Parkinson’s disease’? For James Ramsay Hunt (1872–1937), writing 100 years ago and 100 years after James Parkinson (1755–1824)—general medical practitioner, apothecary, geologist, palaeontologist and political activist—described ‘involuntary tremulous motion, with lessened muscular power, in parts not in action or even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace; the senses and intellects being uninjured’ in the inhabitants of Hoxton Square, East London, none of these is entirely correct. Parkinson’s model of exactness and clarity of expression is ‘merely a delineation by means of which a certain group of cases [can] readily be recognised and differentiated… a syndrome… which may be caused by a variety of pathological...

Brain 2017

A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies

Abstract

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype–phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more ‘conventional’ ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype–phenotype correlations that are important for genetic counselling and of possible prognostic value.

Brain 2017

Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study

Summary

Background

Degenerative processes in neurodegenerative diseases can start years before clinical manifestation. We aimed to establish whether a multiple sclerosis prodromal period exists by examining patterns of health-care use before a first demyelinating event.

Methods

In this matched cohort study, we used data from linked health administrative and clinical databases from four Canadian provinces (British Columbia, Saskatchewan, Manitoba, and Nova Scotia) to compare hospital, physician, and prescription use data from people with multiple sclerosis and matched general population controls in the 5 years before the first demyelinating disease claim (health administrative index date) or clinically reported symptom onset (clinical index date). Rate ratios (RRs) were estimated using negative binomial regression and combined across provinces using random effect models. The primary outcome was all-cause use of health care during each of the 5 years before the health administrative or clinical index date.

Findings

The health administrative cohort included 14 428 multiple sclerosis cases and 72 059 matched controls for whom data were available between April, 1984, and April, 2014. Annual health-care use increased steadily between 5 years and 1 year before the first demyelinating disease claim in people with multiple sclerosis compared with controls (from RR 1·26 [95% CI 1·16–1·36] to 1·78 [1·50–2·10] for hospital admissions; from 1·24 [1·16–1·32] to 1·88 [1·72–2·07] for physician claims; and from 1·23 [1·06–1·41] to 1·49 [1·41–1·59] for prescriptions, assessed as drug classes). Similar patterns for physician claims and prescriptions were observed in the cohort with available clinical symptom onset (3202 individuals with multiple sclerosis and 16 006 controls), although the differences in use in each of the 5 years mostly did not reach statistical significance.

Interpretation

More frequent use of health care in patients with multiple sclerosis than in controls in the 5 years before a first demyelinating event, according to health administrative data, suggests the existence of a measurable multiple sclerosis prodrome. These findings have clinical and research implications, including the establishment of an earlier window of opportunity to identify and potentially treat multiple sclerosis.

Lancet Neurology 2017

Outcomes after intracerebral hemorrhage from arteriovenous malformations

ABSTRACT

Objective: To compare outcomes after intracerebral hemorrhage (ICH) from cerebral arteriovenous malformation (AVM) rupture and other causes of ICH.

Methods: We performed a retrospective population-based study using data from the Nationwide Inpatient Sample. We used standard diagnosis codes to identify ICH cases from 2002 to 2011. Our predictor variable was cerebral AVM. Our primary outcomes were inpatient mortality and home discharge. We used logistic regression to compare outcomes between patients with ICH with and without AVM while adjusting for demographics, comorbidities, and hospital characteristics. In a confirmatory analysis using a prospective cohort of patients hospitalized with ICH at our institution, we additionally adjusted for hematoma characteristics and the Glasgow Coma Scale score.

Results: Among 619,167 ICH hospitalizations, the 4,485 patients (0.7%, 95% confidence interval [CI] 0.6–0.8) with an AVM were younger and had fewer medical comorbidities than patients without AVM. After adjustment for confounders, patients with AVM had lower odds of death (odds ratio [OR] 0.5, 95% CI 0.4–0.7) and higher odds of home discharge (OR 2.0, 95% CI 1.4–3.0) than patients without AVM. In a confirmatory analysis of 342 patients with ICH at our institution, the 34 patients (9.9%, 95% CI 7.2–13.6) with a ruptured AVM had higher odds of ambulatory independence at discharge (OR 4.4, 95% CI 1.4–13.1) compared to patients without AVM.

Conclusions: Patients with ICH due to ruptured AVM have more favorable outcomes than patients with ICH from other causes.

Neurology 2017

Risks and benefits of clopidogrel–aspirin in minor stroke or TIA Time course analysis of CHANCE

ABSTRACT

Objective: To investigate the short-term time course risks and benefits of clopidogrel with aspirin in minor ischemic stroke or TIA.

Methods: Data were derived from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial. The primary outcome was a new ischemic stroke. Safety outcomes included any bleeding and moderate to severe bleeding. Time course analyses were performed for the outcomes of both stroke and bleeding.

Results: A total of 145 (71.1%), 13 (6.4%), and 12 (5.9%) of 204 new ischemic strokes in the clopidogrel–aspirin group vs 223 (75.6%), 19 (6.4%), and 8 (2.7%) of 295 in the aspirin alone group occurred at the first, second, and third week, respectively. A total of 23 (38.3%), 15 (25.0%), and 9 (15.0%) of 60 bleeding cases in the clopidogrel–aspirin group vs 15 (36.6%), 8 (19.5%), and 3 (7.3%) of 41 in the aspirin alone group occurred at the first, second, and third week, respectively. Clopidogrel–aspirin treatment numerically reduced the risk of ischemic stroke within the first 2 weeks. From the 10th day, the number of any bleeding cases caused by dual antiplatelets outweighed that of new stroke reduced by dual antiplatelets.

Conclusions: Clopidogrel–aspirin treatment may have a benefit of reducing stroke risk outweighing the potential risk of increased bleeding especially within the first 2 weeks compared with aspirin alone in patients with minor stroke or TIA.

Neurology 2017

Diagnostic value of prehospital ECG in acute stroke patients

ABSTRACT

Objective: To investigate the diagnostic yield of prehospital ECG monitoring provided by emergency medical services in the case of suspected stroke.

Methods: Consecutive patients with acute stroke admitted to our tertiary stroke center via emergency medical services and with available prehospital ECG were prospectively included during a 12-month study period. We assessed prehospital ECG recordings and compared the results to regular 12-lead ECG on admission and after continuous ECG monitoring at the stroke unit.

Results: Overall, 259 patients with prehospital ECG recording were included in the study (90.3% ischemic stroke, 9.7% intracerebral hemorrhage). Atrial fibrillation (AF) was detected in 25.1% of patients, second-degree or greater atrioventricular block in 5.4%, significant ST-segment elevation in 5.0%, and ventricular ectopy in 9.7%. In 18 patients, a diagnosis of new-onset AF with direct clinical consequences for the evaluation and secondary prevention of stroke was established by the prehospital recordings. In 2 patients, the AF episodes were limited to the prehospital period and were not detected by ECG on admission or during subsequent monitoring at the stroke unit. Of 126 patients (48.6%) with relevant abnormalities in the prehospital ECG, 16.7% received medical antiarrhythmic therapy during transport to the hospital, and 6.4% were transferred to a cardiology unit within the first 24 hours in the hospital.

Conclusions: In a selected cohort of patients with stroke, the in-field recordings of the ECG detected a relevant rate of cardiac arrhythmia. The results can add to the in-hospital evaluation and should be considered in prehospital care of acute stroke.

Neurology 2017