Thomas O. Crawford

Toxic neuropathy in patients with pre-existing neuropathy

The authors report significant worsening of a pre-existing neuropathy in six patients who received “non-toxic” dosages of known neurotoxic agents. Before treatment, baseline total neuropathy score (TNS) averaged 9.5 (range 0 to 19). After chemotherapy (Taxol [125 to 175 mg/m2 × 4]; vincristine [2 to 5 mg]; cisplatin [40 mg/m2 × 8]; and thalidomide [60 g]), the TNS averaged 22 (range 13 to 29). The authors conclude that functionally disabling toxic neuropathy can occur in patients with pre-existing neuropathy at standard doses.

SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Background Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Methods Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of “sitters” (cohort 1) and an ambulatory group of “walkers” (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2–8 years of age. Sixty-one subjects were randomized 1∶1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. Results At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (differenceu200a=u200a0.643, 95% CIu200a=u200a−1.22–2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (pu200a=u200a0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (pu200a=u200a0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (pu200a=u200a0.007). Conclusions This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials. Trial Registry Clinicaltrials.gov NCT00227266

Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons.

Expression of the nerve growth factor receptor (NGF-R) mRNA in adult motor neurons is increased by axonal injury. The present study was designed to examine, by immunocytochemistry, the onset, course, and specificity of NGF-R up-regulation following distal or proximal crush of the sciatic nerve. Lesions at both levels induced the appearance of NGF-R-like immunoreactivity in motor neurons beginning on day two postaxotomy. NGF-R-like immunoreactivity was present exclusively in axotomized neurons, as verified by the near complete colocalization of immunoreactive NGF-R with a fluorescent retrograde tracer injected at the crush site. NGF-R expression was closely linked with disconnection of cells from the target; one week after muscle reinnervation, NGF-R immunoreactivity was no longer detectable in animals with distal injuries. These results extend the previous findings of axotomy-induced expression of NGF-R mRNA to the level of the receptor. Furthermore, our observations are consistent with the hypothesis that target-derived factors participate in the regulation of NGF-R gene expression in adult motor neurons.

Heterogeneity of nemaline myopathy cases with skeletal muscle α-actin gene mutations†

Nemaline myopathy (NM) is the most common of several congenital myopathies that present with skeletal muscle weakness and hypotonia. It is clinically heterogeneous and the diagnosis is confirmed by identification of nemaline bodies in affected muscles. The skeletal muscle α‐actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM. We have screened the ACTA1 gene in a cohort of 109 unrelated patients with NM. Here, we describe clinical and pathological features associated with 29 ACTA1 mutations found in 38 individuals from 28 families. Although ACTA1 mutations cause a remarkably heterogeneous range of phenotypes, they were preferentially associated with severe clinical presentations (p < 0.0001). Most pathogenic ACTA1 mutations were missense changes with two instances of single base pair deletions. Most patients with ACTA1 mutations had no prior family history of neuromuscular disease (24/28). One severe case, caused by compound heterozygous recessive ACTA1 mutations, demonstrated increased α‐cardiac actin expression, suggesting that cardiac actin might partially compensate for ACTA1 abnormalities in the fetal/neonatal period. This cohort also includes the first instance of an ACTA1 mutation manifesting with adult‐onset disease and two pedigrees exhibiting potential incomplete penetrance. Overall, ACTA1 mutations are a common cause of NM, accounting for more than half of severe cases and 26% of all NM cases in this series. Ann Neurol 2004;56:86–96

SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

Background Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. Methods This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Results Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. Conclusions This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. Trial Regsitration Clinicaltrials.gov NCT00227266

Ocular motor abnormalities in ataxia telangiectasia.

Although abnormal eye movements are a prominent feature of ataxia telangiectasia, the characteristics of the oculomotor dysfunction in the disease have been reported only in small groups of patients. We have examined eye movements clinically in 56 patients with ataxia telangiectasia, and obtained electrooculographic recordings of eye movements in 33 subjects. Deficits were observed in the eye movement systems that stabilize images on the retina, including pursuit, gaze holding, convergence, vestibular and optokinetic slow phases, and cancellation of vestibular slow phases. Abnormalities in the systems that maintain fixation and shift gaze were also prominent, including abnormal reflexive and voluntary saccades (characterized by prolonged latency, hypometric amplitude, and the use of head movements to initiate gaze shifts), impaired fixation, and a reduction in vestibular and optokinetic quick phases. The abnormalities in image stabilization most likely result from dysfunction in the cerebellar flocculus and paraflocculus. The basis of the saccadic and fixation disturbance is less certain but may be the result of abnormal supranuclear control of the superior colliculus resulting from dysfunction in the cerebellar vermis or the basal ganglia.

Ocular manifestations of ataxia-telangiectasia ☆

PURPOSEnTo report the manifestations of ataxia-telangiectasia (A-T) on the ocular sensory and motor systems.nnnDESIGNnA prospective observational case series.nnnMETHODSnIn a single tertiary care institition, a comprehensive ophthalmologic evaluation was made of patients with A-T as part of a systemic/neurologic evaluation. Sixty-three A-T patients between the ages of 2 and 28 years were examined.nnnRESULTSnIn 58 A-T patients whose visual acuity could be measured, best-corrected visual acuity in the better eye was 20/20 to 20/30 in 39 (67%), 20/40 to 20/50 in 17 (29%), and 20/60 to 20/80 in 2 (4%). The mean geometric visual acuity of the better eye was 20/31. Telangiectatic vessels were seen in the bulbar conjunctiva in 57 of 63 patients (91%) and on the skin of the face of 21 patients (33%). Twenty-four of 63 patients (38%) had strabismus. Esodeviations were the most common, seen in 15 individuals. Apraxia of horizontal gaze was observed in 19 of 63 patients (30%). Hypometric saccades were evident in 48 (76%), pursuit abnormalities in 43 (63%), and nystagmus in 18 (29%). Accommodation was deficient in the 54 patients in whom it was measured. No posterior segment vascular anomalies were detected.nnnCONCLUSIONSnVisual acuity of 20/50 was present in 96% of the patients we examined. Telangiectatic vessels on the bulbar conjunctiva were seen in nearly every patient, though these are of no functional significance. Ocular motor abnormalities, especially strabismus, are a common finding in A-T. Poor accommodation and abnormal eye movements may lead to reading difficulty reported by patients with A-T.

Neurofilament distribution and organization in the myelinated axons of the peripheral nervous system

The nature of neurofilament organization within the axonal cytoskeleton has been the subject of controversy for many years. Previous reports have suggested that neurofilaments are randomly distributed in the radial dimension of the myelinated axon. Randomness of distribution implies that there is no interaction between neurofilaments, while order in distribution suggest the presence of forces between neurofilaments. To address the issue of randomness vs. order, we evaluated neurofilament distribution by two different statistical approaches--nearest-neighbor distance and the Poisson tile-counting method. Neurofilament nearest-neighbor distances in a myelinated axon differ from nearest-neighbor distances of a set of random points with similar density (40.6 +/- 7.0 nm vs. 30.7 +/- 12.9 nm, P < 0.0001). The Poisson tile-counting method also indicated that neurofilament distribution is different from a random distribution, under conditions of appropriate tile size and masking of other organelles. To further characterize the distribution of neurofilaments, we compared the relationship between nearest-neighbor distance and density for three sets of data: evenly spaced points, randomly distributed points and measured neurofilament coordinates. Neurofilaments do not conform to either evenly spaced or random distribution models. Instead, neurofilament distribution falls into an intermediate position between evenly spaced and random distributions. This study also demonstrates that the nearest-neighbor distance method of assessing neurofilament distribution offers several technical and theoretical advantages to the Poisson tile-counting method.

Ataxia-telangiectasia : Mild neurological presentation despite null ATM mutation and severe cellular phenotype

Ataxia‐telangiectasia (A‐T) is an autosomal recessive disorder characterized by progressive neurodegeneration, immunodeficiency, susceptibility to cancer, genomic instability, and sensitivity to ionizing radiation. A‐T is caused by mutations that eliminate or inactivate the nuclear protein kinase ATM, the chief activator of the cellular response to double strand breaks (DSBs) in the DNA. Mild A‐T is usually caused by ATM mutations that leave residual amounts of active ATM. We studied two siblings with mild A‐T, as defined by clinical examination and a quantitative A‐T neurological index. Surprisingly, no ATM was detected in the patients cells, and sequence analysis revealed that they were homozygous for a truncating ATM mutation (5653delA) that is expected to lead to the classical, severe neurological presentation. Moreover, the cellular phenotype of these patients was indistinguishable from that of classical A‐T: all the tested parameters of the DSB response were severely defective as in typical A‐T. This analysis shows that the severity of the neurological component of A‐T is determined not only by ATM mutations but also by other influences yet to be found.

Stimulation single-fiber EMG in infant botulism.

The principal electrodiagnostic feature of infant botulism, an incremental response on high rates of repetitive nerve stimulation, has variable sensitivity and may not always be useful as a diagnostic test given the vagaries of test timing and severity of illness. We report the use of stimulation single fiber EMG (S‐SFEMG) in making this clinical diagnosis. Four infants between 1 and 5 months of age presented with rapidly progressive bulbar and limb weakness, internal and external ophthalmoplegia, areflexia, and compromised ventilation. Incremental response with high‐rate repetitive nerve stimulation and a typical clinical course for infant botulism confirmed the diagnosis in all; stool toxin studies were positive for type B botulinum in 2 of the 3 cases in which they were obtained. S‐SFEMG was performed by surface stimulation of median and ulnar nerves and recording with a single fiber needle in the thenar, hypothenar, or first dorsal interosseous muscles. A total of eight single fiber recordings were studied at rates of 2, 5, 10, and 20 Hz. All single fibers studies showed an improvement with higher rates of stimulation, beginning at 10 Hz and peaking at 20 Hz. Compared to baseline study at 2 Hz (100%), the mean percent changes in jitter at 5, 10, and 20 Hz were 109, 60, and 47, respectively. This is the first report of the usefulness of S‐SFEMG in the diagnosis of infant botulism.