The origin and nature of beading: a reversible transformation of the shape of nerve fibers.

Nerve fibers which appear beaded (varicose, spindle-shaped, etc.) are often considered the result of pathology, or a preparation artifact. However, beading can be promptly elicited in fresh normal nerve by a mild stretch and revealed by fast-freezing and freeze-substitution, or by aldehyde fixating at a temperature near 0 degree C (cold-fixation). The key change in beading are the constrictions, wherein the axon is much reduced in diameter. Axoplasmic fluid and soluble components are shifted from the constrictions into the expansions leaving behind compacted microtubules and neurofilaments. Labeled cytoskeletal proteins carried down by slow axonal transport are seen to move with the soluble components and not to have been incorporated into and remain with, the cytoskeletal organelles on beading the fibers. Lipids and other components of the myelin sheath are also shifted from the constrictions into the expansions, with preservation of its fine structure and thickness. Additionally, myelin intrusions into the axons are produced and a localized bulging into the axon termed "leafing". The beading constrictions do not arise from the myelin sheath: beading occurs in the axons of unmyelinated fibers. It does not depend on the axonal cytoskeleton: exposure of nerves in vitro to beta, beta'-iminodipropionitrile (IDPN) disaggregates the cytoskeletal organelles and even augments beading. The hypothesis advanced was that the beading constrictions are due to the membrane skeleton; the subaxolemmal network comprised of spectrin/fodrin, actin, ankyrin, integrins and other transmembrane proteins. The mechanism can be activated directly by neurotoxins, metabolic changes, and by an interruption of axoplasmic transport producing Wallerian degeneration.

Parathyroid storm.

Primary hyperparathyroidism frequently has a chronic and relatively benign course. Occasionally, however, it may have a stormy presentation requiring prompt adequate diagnosis and urgent surgical treatment. We describe a 71-year-old woman who had severe hypercalcemia, seizures, and coma refractory to treatment with anticonvulsant drugs, intravenous infusion of normal saline, furosemide, glucocorticoids, calcitonin, and hemodialysis. Bone roentgenograms were normal, but a strikingly positive bone scan that also showed marked soft-tissue uptake prompted the diagnosis of primary hyperparathyroidism and the successful surgical removal of a large parathyroid adenoma. This was followed by a remarkable recovery and marked reduction in soft-tissue radioactive uptake on bone scan. The association of hypercalcemia and seizures and the diagnostic value of bone scanning are discussed. An up-to-date review of the literature is presented. We proposed this condition to be named "parathyroid storm" on the basis of the rapid and lethal course unless surgery is performed without delay.

Late-onset Mcardle's disease with unusual electromyographic findings.

Symptoms of McArdle's disease (muscle phosphorylase deficiency) commonly begin in childhood or adolescence. Late onset of the disease is rare. We describe a 76-year-old man whose symptoms began at age 74 years with sudden onset of proximal muscle weakness and fatigability. Electromyography disclosed substantial spontaneous activity and myopathic features as seen in inflammatory muscle disease. The diagnosis of McArdle's disease was made by histochemical studies of muscle, an abnormal ischemic lactate test, and absence of myophosphorylase activity.

Electrophysiologic evaluation of diaphragm by transcutaneous phrenic nerve stimulation.

Phrenic nerve function was evaluated by transcutaneous stimulation in the neck and recording the diaphragmatic potential from surface electrodes placed at the ipsilateral seventh intercostal space (7CS) and the xiphoid process (XP). Simultaneous recordings from 7CS and XP electrodes connected together (XP-7CS) and each connected to a remote reference (knee-7CS and knee-XP) disclosed that the 7CS electrode was always more active and showed electropositive activity, whereas the XP electrode, which was only minimally active, showed electronegative response. Out-of-phase summation of opposite polarity activity at the two electrodes resulted in a higher amplitude response in XP-7CS derivation. Phrenic nerve studies are useful in establishing phrenic nerve injury following cardiothoracic operation. They may also provide evidence of phrenic nerve or diaphragmatic involvement in demyelinative neuropathies, motor neuron disease, and muscular dystrophies.

The relation of the beading of myelinated nerve fibers to the bands of Fontana.

The bands of Fontana, appearing as spirals or irregular light and dark strips crossing the surface of unstretched nerves, are due to the wavy disposition of nerve fibers within the epineural-perineural sheaths. A mean tension of 2.7 +/- 0.23 (S.E.M.) g applied to segments of rat tibial nerves straightens the fibers and unbands the nerves causing them to lengthen by 9.35 +/- 0.89%. The nerves cold-fixed in situ at that point showed the myelinated fibers to be beaded. On relaxation the nerves rebanded and the fibers were no longer beaded. The tension at which unbanding occurred was better determined when the epineural-perineural sheaths were slit longitudinally. Under these conditions, unbanding occurred at a mean tension of 0.59 +/- 0.08 g and the nerves lengthened by 8.56 +/- 0.58%. The lengthening was not statistically different from that seen in sheathed nerves. In preparations with the epineural-perineural sheaths removed, banding was lost with tensions of 0.20 +/- 0.03 g and the nerves lengthened by 12.1 +/- 1.04%. The tensions needed were significantly lower than that for the sheathed and slit-sheath nerve groups. When cold-fixed, when banding was lost, the fibers were seen to be beaded. Banding of the desheathed nerves returned on relaxation of the nerves. However, after tensions of 8 g they showed plasticity in which the ends of the nerves needed to be pushed together to initiate rebanding in comparison to sheathed or sheath-slit nerves which rebanded spontaneously following relaxation after even higher tensions of 40 g. At the highest tensions the nerves remained extended and could not be forcibly rebanded.(ABSTRACT TRUNCATED AT 250 WORDS)

Origin of beading constrictions at the axolemma: presence in unmyelinated axons and after beta,beta'-iminodipropionitrile degradation of the cytoskeleton.

Myelinated nerve fibres become beaded when nerves are subjected to a mild stretch; the beading is seen as varicosities, a series of alternating constrictions and enlargements, when using freeze-substitution or cold-fixation to hold this labile form change in place during fixation. One possibility for how this form change comes about is that the myelin sheath or its Schwann cell initiates beading. We now report, however, that a similar beading is seen in the axons of unmyelinated fibres. In electron micrographs, longitudinal sections of axons show the series of constrictions and expansions typical of beading. In cross-sections, axons with unusually small diameter, corresponding to the constrictions, are seen to contain closely packed microtubules and neurofilaments while neighbouring swollen axons with widely dispersed microtubules correspond to the beading expansions. Another possibility for the form change is that the cytoskeleton is responsible for beading. We discovered that direct exposure of nerves to beta, beta'-iminodipropionitrile in vitro for 1-6 h causes both axonal microtubules and neurofilaments to become degraded and replaced by an amorphous residue. Nevertheless, beta,beta'-iminodipropionitrile-treated nerves show constrictions in myelinated fibres when stretched. An even greater degree of beading with narrower and longer constrictions appears in some fibres, with the expanded regions having oblate ends giving the appearance of a string of sausages. In cross-sections taken through the constrictions, a greater than usual reduction of axonal area was seen, this was due to the loss of cytoskeletal organelles which would act to limit the degree of constriction. With longer exposure to beta, beta'-iminodipropinitrile more fibres show complete degeneration of the cytoskeleton and form ovoids typical of Wallerian degeneration. Unmyelinated axons of beta, beta'-iminodipropionitrile-treated nerves which showed degeneration of their cytoskeleton with its replacement by amorphous material still demonstrated beading. As neither the myelin sheath nor the intact cytoskeleton within the axon is necessary for beading, by exclusion, we consider beading constrictions to be initiated at the level of the axolemma. In our hypothesis the membrane skeleton is responsible; namely, the spectrin, actin and other molecular species lining the inside of the axolemma and binding to transmembrane proteins. The membrane skeleton may be activated by stretch via transmembrane proteins (e.g. beta 1-integrins). The membrane skeleton mechanism may also be directly engaged in the production of Wallerian degeneration or be induced by neurotoxic agents.

The beaded form of myelinated nerve fibers.

When the nerves are lightly stretched and fixed by freeze-substitution, their fibers show the form-change termed "beading" which consists of a series of undulating constrictions and swellings in the internodes. This form change has not ordinarily been seen in chemically fixed nerves, or when it has, it has been ascribed to a pathological change or an artifact. We now report that beading is also retained in normal nerves when, following a light maintained stretch, they are fixed with aldehydes at a temperature close to 0 degrees C. The degree of beading in single fibers teased from the aldehyde fixed nerves was graded and found to be maximal at 0 degrees C, falling off with increased temperature until, at temperatures above 16 degrees C, most fibers showed no beading or a very mild beading. The fibers of nerves cold-fixed at 0 degrees C displayed the characteristics as freeze-substituted fibers, but with a somewhat smaller number of maximally beaded fibers and an 18% reduction in microtubule numbers in the axons. Desheathing or slitting the sheaths of the nerves before cold-fixation increased the probability of retaining beading. Exposure of stretched nerves to the aldehyde fixative at room temperatures for times as short as 3-5 min before they were cold-fixed showed a diminished degree of beading, indicating that aldehydes can have a deleterious effect on the beading mechanism which we hypothesize to be present in the fiber. This action is distinct from the general cross-linking action of aldehydes.

Long-term tracheostomy ventilation in neuromuscular diseases: patient acceptance and quality of life.

Domiciliary assisted ventilation has been used to prolong life in patients with neuromuscular diseases. Although earlier studies suggest that the majority of patients are satisfied with their lives, the physician's perception of a patient's poor quality of life on assisted ventilation is a major reason for discouraging assisted ventilation. In this study, the quality of life was assessed in 19 patients with neuromuscular diseases on domiciliary tracheal intermittent positive-pressure ventilation for a mean duration of 54 months. An attempt was made to compare the quality of life of Duchenne muscular dystrophy patients with that of amyotrophic lateral sclerosis patients. More than two-thirds of patients were satisfied with their lives. Eighty-four percent thought they had made the right choice. Patients with amyotrophic lateral sclerosis were somewhat more negative or ambiguous toward assisted ventilation and had lower life satisfaction scores as compared with Duchenne muscular dystrophy patients. Financial stresses were significant. Assisted ventilation should be offered as a viable option to patients with neuromuscular diseases. Larger studies may be useful in influencing insurance companies to make expenses associated with assisted ventilation reimbursable.

Diabetic neuropathy.

The most common form of diabetic neuropathy is chronic, distal symmetrical sensorimotor, or predominantly sensory neuropathy; the latter is invariably associated with some degree of autonomic dysfunction. There are, however, other neuropathic patterns in diabetes mellitus that are uncommon but are important to recognize, since they may mimic many other non-neurologic diseases. This article discusses a variety of forms of mononeuropathies and diabetic proximal motor neuropathy, commonly known as diabetic amyotropy.

Metabolic myopathies. A diagnostic evaluation.

This article briefly reviews the initial approach to the patient suspected of having metabolic myopathy. Diagnostic highlights include relevant points of history, physical examination, blood work-up, forearm ischemic exercise test, electrophysiologic testings and muscle biopsy. The diagnostic evaluation is discussed in detail in separate articles.

Toxic myopathies.

Toxic myopathies may occur with a variety of prescribed medications, illicit drug abuse, or other toxins. The article discusses an overview of some of the compounds that may cause myopathy, the clinical and laboratory features, histology, mechanisms of action, and potential risk factors of myopathy. The ability to recognize these syndromes is essential to avoid unnecessary tests and to avoid delay in treatment, especially in critically ill patients or patients with other neuromuscular diseases.

Endocrine myopathies.

This article provides a review of some of the muscular disorders that can arise from some of the commonly seen endocrinologic disturbances. Thyroid, parathyroid, and adrenal dysfunctions as they relate to neuromuscular symptoms are discussed. Common clinical presentations of the endocrine myopathies are highlighted, along with diagnostic evaluation and treatments.

Burst-suppression pattern with unusual clinical correlates.

A 44-year-old man suffered a severe anoxic encephalopathy with rapid fatal outcome. His EEG prior to expiration showed a burst-suppression pattern (BSP) with occurrence of two previously unreported clinical features: spontaneous chewing movements during the burst and tonic posturing during the suppression phase. In coma the appearance of BSP in the EEG commonly implies a severe anoxic/metabolic insult to the brain with a grave prognosis. The pattern is considered to be interictal, except in cases presenting with myoclonic status epilepticus. Subtle intermittent movements of the eye, mouth and cardiovascular rhythm are uncommon and it is unclear whether these are epileptic events or not. This case indicates that the suppression phase can also have associated clinical signs.

The significance of amplitude asymmetry in clinical electroencephalography.

Forty-two EEG recordings with bilateral generalized slow background activity, but asymmetric because of suppression of the amplitude over one hemisphere, were selected for the study. This pattern was prospectively correlated with neurological findings as well as neuroimaging techniques. In 76% of cases, the suppression of the amplitude could be lateralized correctly to the site of cerebral insult. It is suggested that: (a) unilateral attenuation of the amplitude of the background EEG correlates highly with ipsilateral focal cerebral acute or subacute large lesion; (b) in cases where bihemispheric slow activity is present, the hemisphere with the lower amplitude is likely to be the site of such a structural lesion; and (c) this study also supports a previous report that amplitude depression has the same pathophysiological significance in EEG as delta activity.

Periodic lateralized EEG abnormality in a case of Neuro-Behcet syndrome.

A thirty-six year old male with a sixteen month history of a progressive neurological disorder had Behcet's disease. His initial electroencephalogram showed periodic lateralizing epileptiform discharges (PLEDs). The electroencephalographic changes in this disorder have not been described in detail in the American literature. The review of world publications in this matter disclosed that there is no specific EEG pattern in this condition, and that electroencephalographic changes are mainly related to the side of the lesion and have no prognostic value.

Midline spike discharges: clinical and EEG correlates.

Thirty-four tracings in 32 patients had spike discharges recorded at Cz and Pz electrodes. Midline spikes showed strong correlations with clinical seizures; 91% had epileptic seizures of diverse types. Over two-thirds of the patients were neurologically impaired. Midline spikes most probably originate from discharging lesions of the mesial or paramedian region of the cerebral cortex.

Myasthenia gravis.

Adult-onset myasthenia gravis is an acquired autoimmune disorder of neuromuscular transmission in which acetylcholine receptor antibodies attack the postsynaptic membrane of the neuromuscular junction. Although the cause of this disease is unknown, the role of immune responses in its pathogenesis is well established. Circulating acetylcholine receptor antibodies are present in 80% to 90% of patients with the generalized form of myasthenia gravis. Most patients have ptosis, diplopia, dysarthria and dysphagia. The weakness and fatigue worsen on exertion and improve with rest. Respiratory muscle and limb weakness are rare at the onset of the disease. For the past two decades, there has been considerable progress in understanding the diagnosis and management of myasthenia gravis. The diagnosis is based on clinical presentation, neurologic examination, and confirmation by means of electrophysiologic testing and immunologic studies. Myasthenia gravis mimics many neuromuscular diseases and even illnesses such as depression and chronic fatigue syndrome. One should always exclude drug-induced myasthenia gravis for all patients. With the introduction of new modalities of treatment, particularly immunosuppressive or immunomodulating drugs, plasma exchange and thymectomy, the morbidity and mortality of myasthenia gravis have decreased dramatically to the point that myasthenia gravis should not be considered as serious a disease as it once was. Although the several therapeutic options are usually effective and have meant independence in daily life to many patients with myasthenia gravis, well-designed, controlled, prospective studies are still lacking.

Seizures and epilepsy in older patients: evaluation and management.

Seizures and epilepsy in older patients are commonly caused by a previous stroke or other organic CNS insult. In patients who have "spells", the first step is to determine whether or not the events are epileptic. Rule out other potential causes of transients loss of consciousness with a careful history, physical exam, lab tests, and imaging studies. An EEG and CT or MRI of the brain are essential. Candidates for treatment with an antiepileptic drug include those with recurrent unprovoked seizures, those with onset of epilepsy presenting with status epilepticus, and those with a strong family history of epilepsy. Monotherapy with a drug known to work best for the type of seizure is preferred. Monitor patients closely for side effects and potential drug-drug interactions.