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Background Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

ObjectiveTo quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.MethodsRetrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.ResultsPatients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.ConclusionTo realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

Objective To rigorously compare automated atlas‐based and manual tracing hippocampal segmentation for accuracy, repeatability, and clinical acceptability given a relevant range of imaging abnormalities in clinical epilepsy. Methods Forty‐nine patients with hippocampal asymmetry were identified from our institutional radiology database, including two patients with significant anatomic deformations. Manual hippocampal tracing was performed by experienced technologists on 3T MPRAGE images, measuring hippocampal volume up to the tectal plate, excluding the hippocampal tail. The same images were processed using NeuroQuant and FreeSurfer software. Ten subjects underwent repeated manual hippocampal tracings by two additional technologists blinded to previous results to evaluate consistency. Ten patients with two clinical MRI studies had volume measurements repeated using NeuroQuant and FreeSurfer. Results FreeSurfer raw volumes were significantly lower than NeuroQuant (P 0.75) for both automated methods. Asymmetry index reproducibility was excellent (>0.75) for manual tracing and FreeSurfer segmentation and fair (0.4–0.59) for NeuroQuant segmentation. Both automatic segmentation methods failed on the two cases with anatomic deformations. Segmentation errors were visually identified in 25 NeuroQuant and 27 FreeSurfer segmentations, and nine (18%) NeuroQuant and six (12%) FreeSurfer errors were judged clinically significant. Interpretation Automated hippocampal volumes are more reproducible than hand‐traced hippocampal volumes. However, these methods fail in some cases, and significant segmentation errors can occur.

Objective Focal cortical dysplasia (FCD) is a common pathology in focal drug resistant epilepsy (DRE). Voxel based morphometric MRI analysis has been proposed as an adjunct to visual detection of FCD, which remains challenging given the subtle radiographic appearance of FCD. This study evaluates the diagnostic value of morphometric analysis program (MAP) in focal DRE with pathology-confirmed FCD. Methods Automated morphometric analysis program analysis generated z-score maps derived from T1 images, referenced to healthy adult or pediatric controls for each of 39 cases with pathology-confirmed FCD. MAP identified abnormal extension of gray matter into white matter (MAP-E) and blurring of the gray-white matter junction (MAP-J), independently of clinical data and other imaging modalities. MRI was visually reviewed by neuroradiologists as part of usual clinical care, and independently re-reviewed retrospectively by a neuroradiologist with >10-years’ experience in epilepsy MRI. Sensitivity and specificity were calculated for MRI, MAP, scalp-EEG, PET and SISCOM compared to resection area (RA). Results In this cohort of 39 histologically proven FCD cases, the sensitivity and specificity of MAP-J [64% (95% CI 48%–77%) and 96% (95% CI 93%–0.98%)] and MAP-E [74% (95% CI 59%–86%) and 94% (95% CI 91%–97%)] were higher than qualitative MRI review, SISCOM, and FDG-PET. Initial MRI review detected FCD in 17, expert review identified 26. Among cases not detected by initial MRI review, MAP-J correctly identified FCD in 12 additional cases and MAP-E in 13 cases. Among cases not detected by expert MRI review, MAP-J correctly identified 6 and MAP-E 8 cases. Excellent surgical outcome was achieved in 76% of patients. Significance MAP showed favorable sensitivity compared to visual inspection and other non-invasive imaging modalities. MAP complements non-invasive imaging evaluation for detection of FCD in focal DRE patients.

A 38-year-old, right-handed woman presented to the epilepsy clinic for evaluation of recurrent spells. These spells are characterized by an aura of a “rushing” cephalic sensation and a sense of “spaciness” or “dizziness” followed by loss of awareness with subsequent amnesia for the event. During these events, the patient is observed by family to sit down and slump forward or fall, followed by hyperventilation and occasionally staring, for up to 3 minutes. There is no head turn, eye deviation, or abnormal body movements. Postictally, she reports generalized weakness without focality and confusion. The spells occurred sporadically for 8 years, but recently increased in frequency to 5 to 20 times per day. Triggers included lack of sleep, stress, and various food products. The patient reported some improvement with levetiracetam therapy at 1,500 mg twice daily.

Background: We compared resting-state functional connectivity (RSFC) among limbic and temporal lobe regions between patients with medial temporal lobe epilepsy (mTLE) and healthy control subjects to identify imaging evidence of functional networks related to seizure frequency, age of seizure onset, and duration of epilepsy. Methods: Twelve patients with drug-resistant, unilateral medial temporal lobe epilepsy and twelve healthy control subjects matched for age, sex, and handedness participated in the imaging experiments. We used network-based statistics to compare functional connectivity graphs in patients with mTLE and healthy controls to investigate the relationship between functional connectivity abnormalites and seizure frequency. Results: Among mTLE patients, we found functional network abnormalities throughout the limbic system, but primarily in the hemisphere ipsilateral to the seizure focus. The RSFCs between ipsilateral hypothalamus and ventral anterior cingulate cortex and between ipsilateral subiculum and contralateral posterior cingulate cortex were highly correlated with seizure frequency. Discussion: These findings suggest that in mTLE, changes in limbic networks ipsilateral to the epileptic focus are common. The pathological changes in connectivity between cingulate cortex, hypothalamus and subiculum ipsilateral to the seizure focus were correlated with increased seizure frequency. This also suggests that cingulate and limbic networks are progressively impacted by increased frequency of seizures, and could even play a central role in the progression of epilepsy.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

ObjectiveTo assess the variation in baseline and seizure onset zone interictal high-frequency oscillation (HFO) rates and amplitudes across different anatomic brain regions in a large cohort of patients.MethodsSeventy patients who had wide-bandwidth (5 kHz) intracranial EEG (iEEG) recordings during surgical evaluation for drug-resistant epilepsy between 2005 and 2014 who had high-resolution MRI and CT imaging were identified. Discrete HFOs were identified in 2-hour segments of high-quality interictal iEEG data with an automated detector. Electrode locations were determined by coregistering the patient's preoperative MRI with an X-ray CT scan acquired immediately after electrode implantation and correcting electrode locations for postimplant brain shift. The anatomic locations of electrodes were determined using the Desikan-Killiany brain atlas via FreeSurfer. HFO rates and mean amplitudes were measured in seizure onset zone (SOZ) and non-SOZ electrodes, as determined by the clinical iEEG seizure recordings. To promote reproducible research, imaging and iEEG data are made freely available (msel.mayo.edu).ResultsBaseline (non-SOZ) HFO rates and amplitudes vary significantly in different brain structures, and between homologous structures in left and right hemispheres. While HFO rates and amplitudes were significantly higher in SOZ than non-SOZ electrodes when analyzed regardless of contact location, SOZ and non-SOZ HFO rates and amplitudes were not separable in some lobes and structures (e.g., frontal and temporal neocortex).ConclusionsThe anatomic variation in SOZ and non-SOZ HFO rates and amplitudes suggests the need to assess interictal HFO activity relative to anatomically accurate normative standards when using HFOs for presurgical planning.

A 74-year-old woman with Parkinson disease was admitted to the hospital for evaluation of dizziness and falls. She had undergone bilateral subthalamic nucleus (STN) implantation of a deep brain stimulator (DBS) 4 years prior to presentation (Activa PC Neurostimulator, model 37601, Medtronic, Minneapolis, MN). Symptoms resulting from Parkinson disease including rigidity and tremor were reasonably controlled with the bilateral STN DBS in addition to carbidopa-levodopa 25–100 mg every 2 hours while awake and 25–100 mg extended release at bedtime. On admission, her vital signs were normal. She was alert and oriented and in no distress, with diffuse moderate rigidity. The next day, on routine nursing assessment, she was found to have tachypnea, tachycardia, and confusion. These assessments were performed every 6 hours; hence onset of her clinical decompensation occurred somewhere between 28 and 34 hours after admission.

Freely available software, derived from the past 2 decades of neuroimaging research, is significantly more flexible for research purposes than presently available clinical tools. Here, we describe and demonstrate the utility of rapidly deployable analysis software to facilitate trainee-driven translational neuroimaging research. A recipe and video tutorial were created to guide the creation of a NeuroDebian-based virtual computer that conforms to current neuroimaging research standards and can exist within a HIPAA-compliant system. This allows for retrieval of clinical imaging data, conversion to standard file formats, and rapid visualization and quantification of individual patients’ cortical and subcortical anatomy. As an example, we apply this pipeline to a pediatric patient’s data to illustrate the advantages of research-derived neuroimaging tools in asking quantitative questions “at the bedside.” Our goal is to provide a path of entry for trainees to become familiar with common neuroimaging tools and foster an increased interest in translational research.

Surgical epilepsy conferences are an important part of the process of determining whether a patient is a candidate for resective epilepsy surgery. At these conferences, repeat review ( re-review ) of the magnetic resonance images (MRIs) of the patient's head often occurs. This study assessed how often radiologic re-review at a presurgical epilepsy conference resulted in a changed interpretation of the head MRI. Charts were reviewed for 239 patients who had been presented at presurgical epilepsy conferences between 2008 and 2012. Of the 233 patients whose MRIs were re-reviewed, resective surgery was performed in 94 patients (40.3%). Forty-one patients (17.6%) had a previously undiagnosed finding, and 18 of the 41 (43.9%) underwent resective surgery. For 4 of the 41 patients (9.8%) with a previously undiagnosed pertinent finding, re-review detected abnormalities that were not amenable to surgical resection (autoimmunity or significant bilateral pathology).

A19-month-old girl of South Indian parents presented to a general pediatric clinic for evaluation of global developmental delay. The infant's father was the maternal uncle of the infant's mother; the maternal greatgrandparents were uncle and niece. The child was delivered at term by cesarean for fetal heart decelerations following an uneventful pregnancy to her primiparous 27-year-old mother. The perinatal course was unremarkable. The infant was able to roll at 3 months of age, but she did not sit independently until 10 months. At 9 months, she had axial hypotonia. By 15 months, she could wave, pull to a stand, and walk with both hands held. She used a pincer grasp at 9 months and ate finger foods at 15 months. At 19 months, she was not walking, even with support, and had stopped sitting, standing, or waving. She started saying

edited by Jean-Marie Saudubray, Georges van den Berghe, and John H. Walter, 684 pp., Springer, 2012, $209 In the 110 years since Sir Archibald Garrod described alkaptonuria, there has been an explosion in our knowledge of metabolic pathways and their derangements. In more recent times, the pace of discovery has quickened exponentially with advances in laboratory science and bioinformatics. For those of us who must sift through this embarrassment of riches for the tools to diagnose and treat our patients, the thicket of syndromes, enzymes, and substrates can be bewildering. The fifth edition of Inborn Metabolic Diseases promises to be highly useful for understanding and treating these disorders.

Neurological Complications of Systemic Cancer and Antineoplastic Therapy edited by Herbert B. Newton, Mark G. Malkin, 590 pp., Informa Healthcare, 2010, $199.95 Nothing offers more diagnostic challenges or therapeutic wrinkles for the consulting neurologist than the oncology unit. Patients have complex, multisystem disease. Therapies have narrow therapeutic windows and side effects that can range from the fulminant and devastating to the insidious and subtle. …

A 58-year-old man presented with daily hour-long spells of hypothermia, hyperhidrosis, and hypotension. Results of laboratory studies, including thyroid-stimulating hormone, free thyroxine, total/bioavailable testosterone, morning cortisol, and urine osmolality, were normal. MRI of the brain