TTX-sensitive and TTX-insensitive sodium channel mRNA transcripts are independently regulated in adult skeletal muscle after denervation.

The expression of mRNA encoding the TTX-sensitive (SkM1) and TTX-insensitive (SkM2) voltage-dependent sodium channels in adult skeletal muscle is independently regulated. In normal skeletal muscle, only the SkM1 message is expressed and the level varies with muscle fiber type. After surgical denervation, the steady-state SkM1 mRNA level declines transiently, but returns to control levels within 5 days. Expression of SkM2 transcripts is markedly activated, reaching a peak 3 days after axotomy and then declining to a maintained level at approximately 30% of peak. Chemical denervation with botulinum toxin results in higher levels of SkM2 mRNA, which by 7 days posttreatment are 7-fold greater than levels in paired axotomized muscles. SkM2 expression subsequently declines as functional reinnervation appears. Quantal acetylcholine release appears to play a major role in suppression of SkM2 expression in adult innervated or reinnervated muscle, whereas nonquantal factors in toxin-treated, but not axotomized, muscle may sustain high level SkM2 mRNA expression.

The effect of hyperglycemia on intracellular calcium in stroke.

The effect of hyperglycemia on cytosolic free calcium ([Ca2+]i) during temporary focal cerebral ischemia was investigated in cats using a fluorometric technique. The middle cerebral artery (MCA) was occluded for a period of 1 h, after which the clip was removed. In seven animals, plasma glucose was raised to 500-700 mg/dl by infusion of a 50% glucose solution starting 30 min after MCA occlusion, while eight animals were kept normoglycemic during and following occlusion. MCA occlusion induced a significant, but identical, elevation of the [Ca2+]i signal ratio (400/506 nm) in both the normoglycemic group (from 1.40 to 1.97 +/- 0.34, p less than 0.01) and in the hyperglycemic group (from 1.40 to 2.00 +/- 0.53, p less than 0.01) at the end of the occlusion. Between 10 and 30 min after reopening, the [Ca2+]i signal ratio decreased to control levels in the normoglycemic group (1.40 +/- 0.11 and 1.36 +/- 0.08 at 10 and 30 min after reopening, respectively), but remained elevated in the hyperglycemic group (1.69 +/- 0.18 and 1.65 +/- 0.21 at 10 and 30 min after reopening, respectively). There was a statistically significant difference between the two groups (p less than 0.01). These data suggest that hyperglycemia may be harmful to calcium recovery during the early recirculation period following focal cerebral ischemia.

Effect of superoxide dismutase on intracellular calcium in stroke.

To clarify the relationship between calcium metabolism and free radical damage during the reperfusion period following ischemia, we investigated the effect of superoxide dismutase (SOD) on changes in cytosolic free calcium, cortical blood flow, and histologic changes following focal cerebral ischemia and reperfusion in 12 cats. Using indo-1, a fluorescent intracellular Ca2+ indicator, we simultaneously measured changes in the Ca2+ signal ratio (400:500 nm), NADH signal (464 nm), and reflectance (340 nm) during ultraviolet excitation (340 nm) directly from the cortex in vivo. The middle cerebral artery (MCA) was occluded for 1 h; only cats in which the EEG amplitude was depressed to less than 10% of control during the occlusion were entered into the study. Starting 2 min prior to release of the occlusion and continuing for 4 min, SOD (10,000 U/kg) was slowly infused in six cats, while in six cats, the vehicle only was infused. During MCA occlusion, the Ca2+ signal ratio increased significantly in both groups with no significant difference between the groups. During reperfusion, the Ca2+ signal ratio remained at a high level in the vehicle-treated group, while in the SOD-treated group, the Ca2+ signal ratio decreased. There was a statistically significant difference between the two groups at 10, 20, and 30 min after reperfusion (p less than 0.01). The histologically damaged area in the SOD-treated group was significantly smaller than that in the vehicle-treated group (p less than 0.01). These data suggest that the histoprotective action of SOD may be due to its ability to attenuate increases in intracellular calcium during the recirculation period following focal cerebral ischemia.

Neurologic manifestations of the organoid nevus syndrome.

Prominent neurologic abnormalities were observed in six patients with epidermal or linear sebaceous nevi (organoid nevi). These cases were remarkable for unilateral facial nevi, cognitive impairment, seizures, and focal or lateralized epileptic EEG abnormalities. Additional manifestations included the onset of seizures in the neonatal period, unilateral hypsarrhythmia or Lennox-Gastaut EEG pattern, hemiparesis, asymmetric macrocephaly, and somatic growth disturbances. The full expression of this disorder was not apparent at birth, but emerged gradually during infancy. The neurologic abnormalities in these patients were attributed to unilateral or asymmetric malformations of the CNS as demonstrated by computed tomography. A lateralized disorder of neuroectodermal proliferation, differentiation, and migration could account for both the cutaneous and neurologic abnormalities in this disorder. The striking clinical similarities in these patients suggest a close link between epidermal and linear sebaceous nevi.

Corticosteroid-responsive dominantly inherited neuropathy in childhood.

We describe three children with corticosteroid-responsive inflammatory demyelinating polyneuropathy from families with dominantly inherited neuropathy. There were atypical clinical, electrophysiologic, and pathologic characteristics that suggested a coexistent inflammatory demyelinating neuropathy and that should alert the clinician to the possibility of an associated acquired, potentially treatable disorder.

Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication.

We examined the sequence of nervous system abnormalities that resulted when rats were given excess amounts of vitamin B6 (pyridoxine). High doses of pyridoxine (1,200 or 600 mg/kg/d) for 6 to 10 days caused a neuronopathy with necrosis of dorsal root ganglion (DRG) sensory neurons, accompanied by centrifugal axonal atrophy and breakdown of peripheral and central sensory axons. Large diameter neurons with long processes and large cytoplasmic volumes were especially affected. Smaller doses (300 to 150 mg/kg/d) for up to 12 weeks had minor effects on DRG neurons, but produced a neuropathy with axonal atrophy and degeneration. Guinea pigs given 1,800 mg/kg/d developed sensory neuronopathy, whereas mice given similar or higher doses did not have neuropathologic abnormalities. Multiple factors including rate of administration, differential neuronal vulnerability, and species susceptibility have bearing on the final expression of pyridoxine neurotoxicity.

A new mutation associated with MELAS is located in a mitochondrial DNA polypeptide-coding gene.

We report a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) who harbored a novel missense mutation at mtDNA position 9957 in the gene specifying subunit III of cytochrome c oxidase (COX III). This T-->C transition converted Phe-251, a highly conserved amino acid in the C-terminus of the polypeptide, to Leu. The mutation, which was not present in 107 normal controls or in 57 patients with various mitochondrial diseases, was heteroplasmic in both muscle and blood of the proband and in blood from his asymptomatic mother. These results provide evidence that the MELAS clinical phenotype can be due not only to mutations in mtDNA-encoded tRNA genes, but in polypeptide-coding genes as well.

Enhanced 2-deoxyglucose incorporation in peripheral nerve during ischemia.

We examined the effect of acute ischemia on peripheral nerve uptake of the glucose analog 2-deoxyglucose (2-DG). Endoneurial 2-DG incorporation was uniform at rest, but increased focally in areas subjected to moderate levels of ischemia which were not severe enough to impair nerve conduction. We believe these data are indicative of increased endoneurial glucose metabolism probably reflecting a compensatory shift to less efficient anaerobic glycolysis. This mechanism may in part account for peripheral nerve's ability to survive transient interruption of its blood supply.

Neuromuscular complications of bone marrow transplantation.

Six children are reported with neuromuscular complications of allogenic bone marrow transplantation. Myositis occurred in 4, chronic inflammatory demyelinating neuropathy in 1, and myasthenia gravis in 1. Chronic graft-versus-host disease was present in 3. The onset following bone marrow transplant may be delayed.

The cerebral palsy patient.

CP is not a disease but rather a descriptive term that identifies a heterogeneous group of children who manifest primarily chronic motor impairment. It should be appreciated that the large group of children identified under this heading have a broad range of associated handicaps. It is also important to recognize that there is an extremely wide range of variability in terms of the degree of impairment each child may exhibit. Therefore, appropriate management strategies and family counseling must be individualized. The importance of communicating with families cannot be overstressed. The management of children will require expertise in many fields. A multidisciplinary approach is therefore preferable for the comprehensive management of children with CP. If a specialized multidisciplinary clinic setting is not available, an "integrated effort coordinator," the primary physician, is essential to optimize care of the child with CP.

Clinical, electrophysiologic, and pathologic evidence for sensory abnormalities in ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Reports of the nature and frequency of sensory nerve involvement in ALS have varied. METHODS: We reviewed the Emory University motor neuron disease registry between 1997 and 2004 to identify 103 patients with ALS without coexisting diseases that might cause sensory abnormalities and for whom electrodiagnostic studies were available for review. Neurophysiologic studies were interpreted based on age-adjusted normative data from our laboratory. Twelve control biopsies were evaluated alongside 22 samples from patients with ALS to ensure blinded evaluation of pathologic specimens. RESULTS: Sensory symptoms or signs were present in 32% of patients, sural sensory nerve action potential amplitudes were abnormal in 27%, and pathologic abnormalities were present in 91% of patients. Large-caliber myelinated fibers were predominantly affected (reduced in 73%) and small-caliber myelinated fibers were affected less often (23%). Thinly myelinated fibers were present in 95% and regenerating clusters in 77% of the biopsies. Teased fiber analysis showed an increased frequency of axonal degeneration and regeneration as well as excessive myelin irregularity. Morphometry confirmed the loss of large-caliber fibers. CONCLUSIONS: These data indicate that one third of patients with amyotrophic lateral sclerosis report sensory symptoms and sural sensory response amplitudes are reduced in a similar proportion of subjects. Pathologic evidence of sensory nerve pathology was present in 91% of patients who underwent sural nerve biopsy. The electrophysiologic and pathologic findings indicate a pattern of axonal loss that predominantly affects large-caliber myelinated fibers.

Immune neuropathies in childhood.

In contradistinction to older populations, immune-mediated disorders (principally demyelinating processes) account for nearly half of peripheral neuropathies in childhood. The largest single diagnostic entity is GBS, which makes up approximately 25% of sensorimotor neuropathies in patients under 18 years of age. The clinical features are similar to those encountered in adults, although the prognosis in youngsters appears to be better than in older populations. Despite the absence of prospective data, plasmapheresis seems to be an effective modality for hastening recovery during GBS in children. The use of human immunoglobulin has gained acceptance for the treatment of GBS in adults, but insufficient data exist to draw firm conclusions about it role in the management of paediatric GBS. CIDP is the second most common cause of chronic sensorimotor neuropathy in children. The clinical manifestations of this disorder are extremely variable, and it can mimic the phenotype of several genetically determined neuropathies. The prognosis in this disorder is also relatively good, although a small number of children have significant neurological disability or treatment side-effects. Other immune-mediated neuropathies are relatively infrequent in our experience. When they occur, they are often associated with collagen-vascular diseases or bone marrow transplantation. Peripheral neuropathy in association with HIV infection in children appears to be rare.

Histopathological features of peripheral nerve and muscle in mitochondrial disease.

Despite enormous strides in the molecular diagnosis of mitochondrial disease, this approach is currently applicable to only a minority of patients who are affected with these disorders. The phenotypic spectrum in this category of disease is large and, in the absence of genotypic confirmation, a pattern recognition paradigm is probably the most sensitive means to reinforce the suspicion of mitochondrial disease. Along with clinical, biochemical, radiographic, and electrophysiological markers, histopathological features from nerve and muscle biopsy are useful indices to factor into a complex equation permitting a presumptive diagnosis or to justify more elaborate diagnostic undertakings. The combination of electrophysiological evidence of demyelinating neuropathy on nerve conduction studies and mild myopathic features on electromyography is one such constellation that should instigate a high index of suspicion for mitochondrial disease. The histopathological hallmarks of mitochondrial cytopathies on muscle biopsy are the "ragged-red fiber" on light level evaluation and paracrystalline inclusions at the electron microscopic level. Neither of these is exclusive to mitochondrial disease and both may be identified among other nonspecific changes seen in biopsy specimens. Histopathological evaluation of muscle and nerve can provide information to reinforce the likelihood of mitochondrial disease or to indicate an alternative diagnosis as the more probable cause of a patient's symptoms.

The role of plasmapheresis in childhood Guillain-Barré syndrome.

Plasmapheresis has been advocated in the treatment of childhood Guillain-Barré syndrome under the assumption that the results of adult series can be extrapolated to children. To test this assumption, we retrospectively evaluated the medical charts of all children who were admitted to The Children's Hospital of Philadelphia between January 1984 and March 1989, with the diagnosis of Guillain-Barré syndrome. Of the 30 patients identified, 7 were excluded because they had mild disease. Of the remaining 23, 9 underwent plasmapheresis and 14 served as historic control subjects. The two groups were similar with respect to age, presenting symptoms, findings on initial physical examination, and antecedent illnesses at the time of diagnosis. The mean time to recover to Grade 2 (independent ambulation) was significantly shorter in the plasmapheresis-treated group, 24.0 +/- 25.4 days, compared to 60.2 +/- 43.6 days in control subjects (mean +/- 1 SD). Our results indicate that plasmapheresis diminishes morbidity in childhood Guillain-Barré syndrome by shortening the interval until recovery of independent ambulation.

Perinatal hypoxic/ischemic spinal cord injury.

We have reviewed our experience in 900 consecutive necropsies performed on infants who died in the first 4 weeks of life. The neuropathologic characteristics of acute hypoxic/ischemic spinal cord injury are described in 21 infants who expired in the perinatal period. Several distinct patterns of spinal cord injury were apparent in asphyxiated neonates. Cord infarction, rare in older age groups, was the commonest lesion and was associated with prematurity and with documented episodes of systemic hypotension. Lumbosacral cord segments were more severely affected, and at affected levels central cord parenchyma was completely necrotic with relative sparing of the periphery. Diffuse neuronal necrosis was more typical of infants delivered at or after term. In these neonates ventromedial neurons were most profoundly injured. Hematomyelia dissecting into spinal cord parenchyma was a consequence of germinal matrix hemorrhage in very premature infants. "Watershed zones" in the cord appear to be most severely affected in these infants. The patterns of spinal cord infarction and the association of this lesion with prematurity and systemic hypotension suggest that the absence or failure of spinal cord blood flow autoregulation may play a role in the etiopathogenesis of perinatal hypoxic/ischemic spinal cord injury.

Dicarboxylic aciduria in an infant with spinal muscular atrophy.

A 1-year-old infant with classic Werdnig-Hoffmann disease was found to excrete abnormally large amounts of dicarboxylic acids in both fed and fasting states, with especially notable increases in the longer-chain (C10 and C12) 3-hydroxydicarboxylic acids. Dicarboxylic aciduria has not previously been associated with Werdnig-Hoffmann disease and suggests a primary or secondary defect of fatty acid metabolism in the disorder.

Teaching in the field: the model of a one-day trip to an outreach clinic.

A trip to an outreach clinic in a 15-passenger van is presented as part of the answer to the forces negatively affecting the practice of academic medicine today. Any subspecialist in a medical center can use the model if a community can be identified that has a hospital or clinic building able to host the university group. County- or state-funded facilities are well suited to a periodic clinic, and public health nurses are well trained in their management. The Muscular Dystrophy Association is a private supporter of clinics like this, allowing specialty doctor visits close to home for patients with disabling weakness who might otherwise be excluded from our increasingly restricted health care system.

Relapse of infant botulism.

We report on 3 infants who had relapse of infant botulism after apparent resolution of clinical symptoms. This group represented 5% of the infants with confirmed infant botulism who were treated at our institution since 1976. The exact cause for these relapses was unclear, but three potential mechanisms are examined. There were no historical, clinical, or electrophysiological predictors of relapse. Although at the time of writing recovery from relapse appeared complete, close follow-up of patients recovering from a bout of infant botulism is necessary.

Clinical electrophysiology of infantile botulism.

Infantile botulism is a recently recognized cause of acute hypotonic paresis and respiratory failure in young infants. Electrophysiological testing has proven useful in early diagnosis in suspected cases by demonstrating abnormal neuromuscular transmission as is known to occur in botulism. Twenty-five infants with bacteriologically proven botulism were studied by uniform methods in our laboratory and characteristic electrophysiological abnormalities were found. Repetitive stimulation at 20 and 50 Hz was the most specific single test; 23 patients (92%) showed incremental responses. Stimulation at low rates was less specific. Concentric needle electromyography provided useful supplemental information. Short-duration, low-amplitude motor unit potentials were prominent in 22 patients (92%) accompanied by abnormal spontaneous activity in 13 patients (54%). Compound muscle action potential amplitudes were usually reduced, but motor and sensory conduction studies were otherwise normal. Electrodiagnostic testing demonstrated one or more characteristic abnormalities in all cases of infantile botulism. This constellation of electrophysiological abnormalities, combined with an appropriate clinical picture, was so distinctive as to allow early presumptive diagnosis of infant botulism, before the results of bacteriological testing were available.