Jeremy M. Shefner

Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy.

Objective: To characterize the motor neuron dysfunction in two models by performing physiologic and morphometric studies. Background: Mutations in the gene encoding cytosolic superoxide dismutase 1 (SOD1) account for 25% of familial ALS (FALS). Transgenes with these mutations produce a pattern of lower motor neuron degeneration similar to that seen in patients with FALS. In contrast, mice lacking SOD1 develop subtle motor symptoms by approximately 6 months of age. Methods: Physiologic measurements, including motor conduction and motor unit estimation, were analyzed in normal mice, mice bearing the human transgene for FALS (mFALS mice), and knockout mice deficient in SOD1 (SOD1-KO). In addition, morphometric analysis was performed on the spinal cords of SOD1-KO and normal mice. Results: In mFALS mice, the motor unit number in the distal hind limb declined before behavioral abnormalities appeared, and motor unit size increased. Compound motor action potential amplitude and distal motor latency remained normal until later in the disease. In SOD1-KO mice, motor unit numbers were reduced early but declined slowly with age. In contrast with the mFALS mice, SOD1-KO mice demonstrated only a modest increase in motor unit size. Morphometric analysis of the spinal cords from normal and SOD1-KO mice showed no significant differences in the number and size of motor neurons. Conclusions: The physiologic abnormalities in mFALS mice resemble those in human ALS. SOD1-deficient mice exhibit a qualitatively different pattern of motor unit remodeling that suggests that axonal sprouting and reinnervation of denervated muscle fibers are functionally impaired in the absence of SOD1.

Lead exposure and amyotrophic lateral sclerosis.

Background. Previous interview-based studies have suggested that exposure to neurotoxicants including metals might be related to ALS. Methods. We evaluated the relation of lead exposure to ALS, using both biological measures and interviews, in a case-control study conducted in New England from 1993 to 1996. Cases (N = 109) were recruited at two hospitals in Boston, MA. Population controls (N = 256) identified by random-digit dialing were frequency-matched to cases by age, sex, and region of residence within New England. Results. Risk of ALS was associated with self-reported occupational exposure to lead (odds ratio [OR] = 1.9; 95% confidence interval [CI] = 1.1–3.3), with a dose response for lifetime days of lead exposure. Blood and bone lead levels were measured in most cases (N = 107) and in a subset of controls (N = 41). Risk of ALS was associated with elevations in both blood and bone lead levels. ORs were 1.9 (95% CI = 1.4–2.6) for each &mgr;g/dl increase in blood lead, 3.6 (95% CI = 0.6–20.6) for each unit increase in log-transformed patella lead, and 2.3 (95% CI = 0.4–14.5) for each unit increase in log-transformed tibia lead. Conclusions. These results are consistent with previous reports and suggest a potential role for lead exposure in the etiology of ALS.

Functional outcome measures as clinical trial endpoints in ALS

The topiramate study was a 12-month randomized placebo-controlled trial in patients with ALS. Follow-up evaluation of the placebo group (n = 97) constituted a well-described cohort of patients with ALS, in whom multiple outcome measures were assessed at 3-month intervals. During the 12-month study period, the decline of forced vital capacity (FVC%) and ALS functional rating scale (ALSFRS) was linear, whereas the decline of maximum voluntary isometric contraction–arm (MVIC-arm) and MVIC-grip Z scores was curvilinear. Rates of FVC% and ALFRS decline, but not of MVIC-arm or MVIC-grip, were independent predictors of survival.

Association of Cigarette Smoking with Amyotrophic Lateral Sclerosis

We explored the relationship between amyotrophic lateral sclerosis (ALS) and cigarette smoking in a case-control study conducted in New England from 1993 to 1996. Recently diagnosed ALS cases (n = 109) were recruited from two major referral centers. Population controls (n = 256) were identified by random telephone screening. Data were analyzed by logistic regression. After adjusting for age, sex, region and education, ever having smoked cigarettes was associated with an increase in risk for ALS (odds ratio 1.7; 95% confidence interval 1.0–2.8). Average cigarettes smoked per day, years smoked and pack-years were all greater in cases than controls, but dose-response trends were not observed. Similar numbers of cases and controls had ever used alcohol, and only a small, nonsignificant association of drinks per month with ALS was observed. The association of cigarette smoking with ALS was not affected by adjusting for alcohol use. In contrast, the weak relationship of ALS with alcohol use was apparently due to confounding by smoking.

A revision of the El Escorial criteria - 2015

There has been much discussion as to the necessity for adjustment of the El Escorial diagnostic criteria, primarily based on observations relating to the specificity of the‘Possible’ category. The ...

Immunotoxin therapy of small-cell lung cancer: a phase I study of N901-blocked ricin.

PURPOSE Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first days dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.

Nerve, muscle, and neuromuscular junction electrophysiology at high temperature

Although the effect of low temperature on the peripheral nervous system has been systematically studied, the effect of high temperature has not. We investigated the effect of elevating limb temperature from 32°C to 42°C by performing sequential motor studies, antidromic sensory studies, and 3‐Hz repetitive stimulation in normal subjects. In addition, we recorded single motor units by using threshold stimulation. On average, motor amplitude and duration decreased by 27% and 19%, respectively, whereas sensory amplitude and duration decreased by 50% and 26%, respectively. Neuromuscular transmission remained normal at 42°C. Single motor unit recordings revealed a reduction in amplitude of 26%, similar to the overall reduction in compound motor amplitude. These findings demonstrate that significant reductions in sensory and motor amplitudes can occur in normal nerves at high temperature; we hypothesize that these changes are secondary to alterations in nerve and muscle ion channel function.

The Effects of Delayed Diagnosis and Treatment in Patients with an Occult Spinal Dysraphism

From 1987 to 1993, 21 older individuals presented for the first time with signs and symptoms that eventually led to the diagnosis of occult spinal dysraphism. Assessment consisted of a neurological examination, urodynamic studies preoperatively and postoperatively, and spinal cord imaging. Of 21 patients 18 had an abnormal neurological examination, whereas only 15 had an abnormal urodynamic study, as judged by sphincter electromyography. Radiological imaging showed that 9 patients had a tethered cord alone, 4 each had lipomeningocele and lipoma, 2 had a bony spine abnormality and 1 each had thoracic meningocele and diastematomyelia. Of the 21 patients 19 underwent spinal surgery. Postoperatively, the neurological examination improved in 1 case (5%) and remained unchanged in 18 (95%), while urodynamic findings improved in 3 (16%), were unchanged in 11 (68%) and worsened in 5 (26%). Six patients had progressive deterioration and required secondary spinal surgery, which helped only 2 (33%). These observations confirm that older children and adults with occult spinal dysraphism are more likely to present with irreversible urological and neurological findings than younger children, and so it is imperative that a diagnosis be made and treatment be instituted as early as possible.

Bladder Functional Changes Resulting from Lipomyelomeningocele Repair

From 1986 to 1991, 12 boys and 23 girls underwent surgery for lipomyelomeningocele removal. Of these patients 29 were 15 months old or younger (average age 3 months), while 6 were 4.5 to 19 years old (average age 10 years). Preoperative and postoperative urodynamic studies, including external urethral sphincter electromyography, were done on everyone. All 29 infants had a cutaneous lesion overlying the lower back and 14 had an abnormal neurological examination. Preoperative urodynamic studies were abnormal in 11 patients, consisting of an upper motor neuron lesion in 6, and a mixed upper and lower motor neuron lesion in 5. Postoperatively, 10 of 14 children with an abnormal neurological examination improved, while 9 of 11 with abnormal lower urinary tract function normalized. In 1 of 18 children (6%) with normal preoperative urodynamic studies detrusor-sphincter dyssynergia developed postoperatively. In all 6 older children urinary incontinence developed, and this led to the diagnosis. Everyone had an abnormal neurological examination and abnormal preoperative urodynamic studies. One child had a lower motor neuron lesion, and 5 had a mixed upper and lower motor neuron lesion. Postoperatively, the neurological examination improved in only 1 patient (16%), and the urological symptoms and urodynamic findings improved in another child. Lipomyelomeningocele has a progressive effect on lower spinal cord function because infants tend to present with fewer urinary manifestations and physical findings than older children. Individuals who escape early detection tend to have a more subtle cutaneous abnormality. As a result, older children are more likely to present with urological and neurological complaints. Surgical correction in infancy provides a degree of reversibility not seen in older children. It is imperative that early identification, evaluation and treatment be undertaken to prevent this progression and permanency of neurological changes and urinary dysfunction.

Reducing intersubject variability in motor unit number estimation.

Motor unit number estimation (MUNE) attempts to directly assess the number of functioning motor units present in a muscle. It is an important addition to the electrodiagnostic evaluation; however, both intrasubject and intersubject reliability must be minimized for this technique to be clinically useful. A number of MUNE techniques have been developed. We propose a change in the way of calculating the MUNE, using the statistical technique described by Daube, and show that this modification reduces intersubject variability and improves test–retest reliability in normal subjects.