Differential impact on motor unit characteristics across severities of adult spinal muscular atrophy.

OBJECTIVE: To test the hypotheses that decomposition electromyography (dEMG) motor unit action potential (MUAP) amplitude and firing rate are altered in SMA; dEMG parameters are associated with strength and function; dEMG parameters are correlated with traditional electrophysiological assessments. METHODS: Ambulatory and non-ambulatory adults with SMA on nusinersen and healthy controls were enrolled. MUAPs were decomposed from multielectrode surface recordings during 30-s maximum contraction of the abductor digiti minimi (ADM). Isometric strength, upper limb function, patient-reported function, and standard electrophysiologic measures of the ADM (compound muscle action potential [CMAP], single motor unit potential [SMUP], motor unit number estimation [MUNE]) were collected. RESULTS: dEMG MUAP amplitudes were higher in ambulatory versus control and non-ambulatory groups and were higher in controls versus non-ambulatory SMA. In contrast, dEMG firing rates were higher in ambulatory versus non-ambulatory and control groups but similar between non-ambulatory and control. dEMG parameters showed moderate to strong positive correlation with strength and function whereas CMAP and MUNE better correlated with function than strength. SMUP did not correlate with strength, function, or dEMG MUAP amplitude. dEMG parameters show overall good test-retest reliability. INTERPRETATION: dEMG provided reliable, noninvasive measure of MUAP amplitude size and firing rate and revealed divergent patterns across disease severity in adults with SMA. Firing rate enhancement, as seen in milder SMA, may provide a therapeutic avenue for improving function in more severe SMA, where firing rates appear preserved. MUAP amplitude size and firing rate, quantified with dEMG, may be promising monitoring biomarker candidates for noninvasive assessment of SMA.

Neurofilament Levels in CSF and Serum in an Adult SMA Cohort Treated with Nusinersen.

OBJECTIVE: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. METHODS: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3-5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n = 6). For patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. RESULTS: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p = 0.0013; pNfH p = 0.0035) and an increase in CSF NfL in controls (p = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r = -0.822, p = 0.04), upper extremity strength (r = -0.828, p = 0.042), lower extremity strength (r = -0.860, p = 0.028), and total strength (r = -0.870, p = 0.024). CONCLUSIONS: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population.

Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen.

OBJECTIVE: Spinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA. METHODS: Participants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement. RESULTS: Data from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (-14.2%±11.5%, n=17) vs baseline (-11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (-13.9%±6.7%) vs baseline (-16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration. CONCLUSION: Adults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA.

Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology. Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment. Results: Six women, seven men (mean age: 37 ± 11, range: 18-59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable. Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy.

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA). Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1-C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded. Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21-64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable. Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

Occipital Nerve Stimulation and Sphenopalatine Ganglion Stimulation for Treatment of Intractable Headache Syndromes.

Headaches are an increasing cause of disability in the world. Intractable headache syndromes affect all age groups but predominantly the middle-aged, working population. Occipital neuralgia is a frequent comorbidity with intractable migraine headaches. Occipital nerve stimulation at the level of nuchal ridge is a reasonable option for these refractory patients. Ultrasound guidance of occipital nerve stimulation can optimize depth placement of leads. Revision surgeries of occipital nerve stimulation are usually performed using surgical leads. Cluster headaches and trigeminal autonomic cephalagias (TACs) are refractory headache conditions that are mediated by sphenopalatine ganglion. Sphenopalatine ganglion stimulation with infrazygomatic approach and fluoroscopic guidance of percutaneous leads can help alleviate pain from cluster headaches and TACs. Innovation in neurostimulation technologies have brought new optimism to these refractory conditions. Efficient and optimal delivery of neurostimulation for intractable headache syndromes requires a multidisciplinary team-based approach for long term compliance and efficacy.

How Are Residents Trained in Neuropathology? A Survey of Neurology Program Directors in the United States.

To understand the current state of neurology residents training in neuropathology, we electronically distributed a 16-item survey to 150 adult and 70 child neurology program directors (PDs). The survey inquired about their program characteristics, neuropathology curriculum and assessment methods, trainee performance, and attitudes. Descriptive analysis was used to summarize categorical variables as frequencies and percentages and continuous as means and standard deviations. We conducted a series of Mann-Whitney U and Fisher's exact tests to evaluate differences between various program characteristics. Sixty-four (29%) PDs responded to the survey, including 45 (30%) adult and 19 (27%) child neurology PDs. Thirty-one programs required a dedicated neuropathology rotation. The majority (92%) used the Residency In-Service Training Examination (RITE) to assess trainee's knowledge. Approximately 86% of the PDs agreed that neuropathology is essential and a defined curriculum is necessary during residency training. There was no difference in the RITE scores between programs. We conclude that a neuropathology rotation was felt to be essential even though the RITE scores did not differ between programs with and without a dedicated rotation. Alternative evaluation and training methods may need consideration. A future survey of all the stakeholders may be required to thoroughly understand and disseminate the neuropathology education well.

Extended disease-free interval of 6 years in a recurrent glioblastoma multiforme patient treated with G207 oncolytic viral therapy.

BACKGROUND: Glioblastoma multiforme (GBM) is a relentless primary central nervous system malignancy that remains resistant to conventional therapy despite major advances in clinical neurooncology. This report details the case of a patient who had failed conventional treatment for recurrent GBM and was ultimately treated with a genetically engineered herpes simplex virus (HSV) type 1 vector, G207. METHODS: Case report detailing the outcomes of one patient enrolled into the gene therapy arm of the Neurovir G207 protocol whereby stereotactic injection of 120 µL G207 viral suspension containing 1×10(7) plaque-forming units (or active viral particles) was made into the enhancing region of the tumor. RESULTS: In this patient, despite aggressive surgical resection, adjuvant radiotherapy and chemotherapy, tumor progression occurred. However, with G207 oncolytic therapy and brief exposures to second and third treatments, this patient had an extended survival time of 7.5 years and a 6-year apparent disease-free interval, an extraordinarily unusual finding in the pretemozolomide era. CONCLUSION: With minimal adjunctive chemotherapy, including one course of temozolomide, one course of procarbazine, and four cycles of irinotecan, the patient survived over 7 years before the next recurrence. Addition of G207 to this patient's traditional therapy may have been the critical treatment producing her prolonged survival. This report demonstrates the potential for long-term response to a one-time treatment with oncolytic HSV and encourages continued research on oncolytic viral therapy for GBM.

Robert Bentley Todd's contribution to cell theory and the neuron doctrine.

Robert Bentley Todd, who is best remembered for "Todd's paralysis," made many more important contributions to neurology and neuroscience, including the concept of brain electricity and electrical discharges in epilepsy. He was also a pioneering microscopist and we here review his neurohistological studies and his contributions to the application of Schwann's (1839) cell theory to the nervous system and the later neuron doctrine, as described in his textbook The Descriptive and Physiological Anatomy of the Brain, Spinal Cord and Ganglions (Todd, 1845), his Cyclopaedia of Anatomy and Physiology (1847) and his joint textbook with William Bowman The Physiological Anatomy and Physiology of Man (1845). Writing in the mid-1840s, Todd acknowledged that the "vesicles" he observed corresponded to the earlier descriptions of "globules" or "kugeln" by Valentin and which Schwann first interpreted as cell bodies. Todd was among the first to recognize that nerve cell bodies were in continuity with axons ("axis cylinders"), sometimes associated with "the white substance of Schwann" ("tubular" fibers), or sometimes without ("gelatinous" fibers). He also described continuous nerve cell branching processes, later called dendrites. He was the first to recognize the insulating properties of Schwann's "white substance" (myelin) to facilitate conduction. Influenced by his contemporary, Faraday, Todd was also the first to develop the functional concept of dynamic polarization ("nervous polarity") to explain nerve cell conduction.

Early optical detection of cerebral edema in vivo.

OBJECT: Cerebral edema is a significant cause of morbidity and mortality in diverse disease states. Currently, the means to detect progressive cerebral edema in vivo includes the use of intracranial pressure (ICP) monitors and/or serial radiological studies. However, ICP measurements exhibit a high degree of variability, and ICP monitors detect edema only after it becomes sufficient to significantly raise ICP. The authors report the development of 2 distinct minimally invasive fiberoptic near-infrared (NIR) techniques able to directly detect early cerebral edema. METHODS: Cytotoxic brain edema was induced in adult CD1 mice via water intoxication by intraperitoneal water administration (30% body weight intraperitoneally). An implantable dual-fiberoptic probe was stereotactically placed into the cerebral cortex and connected to optical source and detector hardware. Optical sources consisted of either broadband halogen illumination or a single-wavelength NIR laser diode, and the detector was a sensitive NIR spectrometer or optical power meter. In one subset of animals, a left-sided craniectomy was performed to obtain cortical biopsies for water-content determination to verify cerebral edema. In another subset of animals, an ICP transducer was placed on the contralateral cortex, which was synchronized to a computer and time stamped. RESULTS: Using either broadband illumination with NIR spectroscopy or single-wavelength laser diode illumination with optical power meter detection, the authors detected a reduction in NIR optical reflectance during early cerebral edema. The time intervals between water injection (Time Point 0), optical trigger (defined as a 2-SD change in optical reflectance from baseline), and defined threshold ICP values of 10, 15 and 20 mm Hg were calculated. Reduction in NIR reflectance occurred significantly earlier than any of the ICP thresholds (p < 0.001). Saline-injected control mice exhibited a steady baseline optical signal. There was a significant correlation between reflectance change and tissue specific gravity of the cortical biopsies, further validating the dual-fiberoptic probe as a direct measure of cerebral edema. CONCLUSIONS: Compared with traditional ICP monitoring, the aforementioned minimally invasive NIR techniques allow for the significantly earlier detection of cerebral edema, which may be of clinical utility in the identification and thus early treatment of cerebral edema.

Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus.

BACKGROUND: Long-term administration of the antifibrinolytic agent epsilon aminocaproic acid (EACA) reduces the rate of rehemorrhage in patients with aneurysmal subarachnoid hemorrhage (SAH), but is associated with cerebral ischemia. OBJECTIVE: To evaluate short-term administration of EACA before early surgery in patients with SAH. METHODS: Retrospective review of 356 patients admitted between June 2002 and December 2007 with a diagnosis of aneurysmal SAH. Medical records were reviewed to determine SAH risk factors, clinical grade at the time of admission, and incidence of rehemorrhage, permanent new-onset focal neurological deficits, computed tomography evidence of cerebral infarction, symptomatic vasospasm, and hydrocephalus. RESULTS: Patients underwent treatment of the ruptured aneurysm an average of 47.4 hours after admission and received an average total dose of 40.6 g of EACA. The mean length of time of administration of EACA was 35.6 hours. There was a total of 5 rehemorrhages, for an overall rebleeding rate of 1.4% and a rate of rehemorrhage per 24-hour period of 0.71%. Overall, the rates of symptomatic vasospasm and permanent neurological deficits attributable to ischemic stroke were 11.5% and 7.2%, respectively, and the incidence of shunt-dependent hydrocephalus was 42.3%. Patients who were treated with coiling had higher rates of symptomatic vasospasm and ischemic complications than patients who had surgery. CONCLUSION: Short-term administration of EACA is associated with rates of rehemorrhage, ischemic stroke, and symptomatic vasospasm that compare favorably with historical controls. The rate of hydrocephalus is relatively high and may be attributable to EACA treatment.

Localization of angiopoietin-1 and Tie2 immunoreactivity in rodent ependyma and adjacent blood vessels suggests functional relationships.

Angiopoietin-1 (Angpt1; previously Ang-1) participates in vascular maintenance and remodeling. In the current study, we investigated the distribution of Angpt1 protein in rat brain. We detected Angpt1 immunoreactivity (IR) in cerebral blood vessels, cuboidal ependyma, and tanycytes, which are specialized hypothalamic bipolar ependymal cells. We also evaluated patterns of IR of endothelium-specific receptor tyrosine kinase 2 (Tie2, the receptor for Angpt1). Tie2 IR was present in Angpt1-immunoreactive cuboidal ependyma in a membranous pattern, suggesting an autocrine or paracrine role for Angpt1-Tie2. Tie2 IR was also associated with peri-ependymal blood vessels, some of which were contacted by tips of Angpt1-immunoreactive tanycyte processes, implying a potential functional ligand-receptor interaction mediating communication between the cerebrospinal fluid and vascular compartments. Because we previously found that cerebral Angpt1 expression was modulated by 17beta-estradiol (E2), and because some tanycyte functions are modulated by E2, we tested the hypothesis that E2 affects ependymal and tanycyte Angpt1 expression in vivo. No gross E2 effect on the ependymal pattern of Angpt1 IR or cerebral Angpt1 protein content was observed.

Tumor-associated epilepsy.

Tumor-associated epilepsy is an important contributor to morbidity in patients with brain tumors. Proposed pathophysiological mechanisms to explain these effects range from neuronal and glial dysfunction to deranged vascular homeostasis, to ionic and pH changes. Perilesional tissue alterations play a vital role in the generation of tumor-associated seizures. Clinical studies have determined that tumor-associated seizures are usually focal with secondary generalization and often resistant to antiepileptic drugs. Tumor histopathological characteristics and location are independent factors that impact seizure burden. Further understanding of the mechanisms of tumor-associated epilepsy may lead to new types of treatments targeted at perilesional tissue alterations.

Estradiol augments peri-infarct cerebral vascular density in experimental stroke.

Peri-infarct increase of vascular density has been observed in animals and in humans with ischemic stroke. Increased peri-infarct vascular density correlates with improved functional outcome after stroke. We hypothesized that pre-treatment with estradiol will increase post-ischemic peri-infarct capillary density in a rat model of transient ischemic stroke. Estradiol, compared to placebo, augmented post-ischemic peri-infarct vascular density by 22% 10 days after stroke. Recovery of forelimb function was not improved with estradiol treatment on day three and nine post-stroke. Loss of estradiol may limit repair in the peri-infarct region by limiting angiogenesis, but functional significance in stroke recovery requires further investigation.