Does peripheral nerve degeneration affect circulatory responses to head-up tilt in spinal cord-injured individuals?

Abstract Despite the loss of centrally mediated sympathetic vasoconstriction, spinal cord-injured (SCI) individuals cope surprisingly well with orthostatic challenges. In the pathophysiology of this intriguing observation spinal sympathetic—, veno-arteriolar—(VAR), and myogenic reflexes seem to play a role. The purpose of this study was to assess whether central (stroke volume, heart rate, blood pressure and total peripheral resistance) and peripheral (leg blood flow, leg vascular resistance and femoral arterial diameter) hemodynamic responses to head-up tilt are different in two groups of SCI patients, i. e., SCI individuals with upper motor neuron lesions (who have spinal reflexes, VAR and myogenic reflexes) (U; n=6) and those with lower motor neuron lesion (who have no spinal reflexes, perhaps no VAR due to nerve degeneration, but intact myogenic reflexes) (L; n=5). Ten healthy male individuals served as controls (C) (normal supraspinal sympathetic control and presence of all reflexes). After 10 min supine rest all individuals were tilted to 30° head-up tilt. Red blood cell velocity (measured by echo Doppler ultrasound) in the femoral artery decreased and vascular resistance increased significantly in all three groups in the upright position compared with supine. Mean arterial pressure (MAP) remained unchanged in U and L and increased significantly in C in the upright versus supine position. The present study shows that all SCI individuals were able to maintain MAP by increasing leg vascular resistance during head-up tilt, despite nerve degeneration in L and lack of centrally mediated sympathetic control in all SCI individuals. Results of the present study suggest that not spinal reflexes but local (myogenic) reflex activity plays a pivotal role in peripheral vascular responses upon head-up tilt when central control mechanisms fail.     

Estrogen reduces the severity of autonomic dysfunction in spinal cord-injured male mice

Autonomic dysreflexia is an autonomic behavioural condition that manifests after spinal cord injury (SCI) and is characterized by acute, episodic hypertension following afferent stimulation below the level of the injury. Common triggers of autonomic dysreflexia include colorectal distension (CRD), and various somatic stimuli. The development of autonomic dysreflexia is dependent, in part, upon the degree of intraspinal inflammation and the resultant spinal neuroplastic changes that occur following SCI. 17beta-estradiol (E) has neuroprotective, anti-inflammatory and smooth muscle relaxant properties, and is therefore a candidate drug for the treatment and/or prevention of autonomic dysreflexia. Autonomic dysreflexia was assessed in adult male mice treated with E. We investigated whether E could be acting centrally by altering: (1) the size of the small diameter primary afferent arbor, (2) the degree of microglia/macrophage infiltration at the site of the injury, or (3) the amount of fibrous scarring present at the injury site. To determine whether E could be working through uncoupling protein-2 (UCP-2), a protein involved with inflammation and regulated by estrogen in some tissues, autonomic dysreflexia was assessed in E-treated adult male mice lacking UCP-2 (UCP-2 KO). 17beta-estradiol was equipotent at reducing autonomic dysreflexia in both UCP-2 KO and WT mice following CRD but not tail pinch. We have shown that E reduces autonomic dysreflexic responses to visceral but not somatic stimulation in male mice independent of the size of the primary afferent arbour, the degree of chronic inflammation, and the presence of UCP-2.     

Focal mucoid degeneration of peripheral nerve

Summary Focal mucoid degeneration was found in a N. suralis biopsy of a 8 year old child, diagnosed clinically and electrophysiologically as progressive muscular atrophy Charcot-Marie-Tooth.     

Autonomic dysfunction in peripheral nerve disease

Autonomic neuropathies are inherited or acquired neuropathies in which autonomic nerve fibers are selectively or disproportionately affected. Generally, sympathetic and parasympathetic fibers are both affected but there are exceptions. Acquired cases can be autoimmune; due to diabetes, amyloidosis, drugs, or toxins; or idiopathic. Autoimmune autonomic neuropathy is often subacute, sometimes associated with a neoplasm, and associated with high titers of antibody to ganglionic nicotinic acetylcholine receptor in about half of the severe cases. The molecular basis of inherited autonomic neuropathies is better known, including recent identification of the loci and genes of hereditary sensory and autonomic neuropathies types I, III, and IV. The inherited amyloid neuropathies are due to mutations of three proteins: transthyretin, apolipoprotein A1, and gelsolin. Non-invasive autonomic testing complements clinical and electrophysiological characterization of the autonomic neuropathies.     

Invited review: autonomic dysfunction in peripheral nerve disease.

The autonomic nervous system is affected in most peripheral neuropathies, but only in a small number of conditions, such as diabetes, amyloidosis, Guillain-Barré syndrome, porphyria, and familiar dysautonomia, is autonomic dysfunction of clinical importance. The pathological changes in the peripheral autonomic nervous system are similar to those in the peripheral somatic nerves. Autonomic disturbances are most likely to occur when there is acute demyelination or damage to small myelinated and unmyelinated fibers. Autonomic investigations should include tests of both sympathetic and parasympathetic function. Treatment consists of management of the underlying cause of peripheral neuropathy, physical and pharmacological measures.     

Focal features in patients with idiopathic generalized epilepsy

Purpose: The stringent dichotomy between focal and generalized epilepsies has become a contentious issue, since neuropathological studies as well as structural and functional imaging data hypothesized the existence of focal brain abnormalities in patients with well-documented idiopathic generalized epilepsy. The aim of our study was to investigate whether clinical and EEG features generally considered typical for a focal seizure disorder also occur in patients with generalized epilepsies to further support the hypothesis of a more continuous transition between focal and generalized epilepsies in contrast to the present concept of a stringent pathophysiologic dichotomy. Methods: We retrospectively studied 20 consecutive patients with idiopathic generalized epilepsy who underwent video EEG monitoring either because of uncertainty of their epilepsy syndrome or because of a difficult to treat epilepsy. We determined the incidence of (a) focal interictal epileptiform discharges (IEDs), (b) intermittent temporal slow waves, and (c) clinical signs that are widely accepted as typical for a focal seizure onset, i.e. version, tonic/dystonic unilateral posturing, postictal hemiparesis, postictal nose wiping and figure of 4. Results: Focal IEDs occurred in seven patients (35.0%), intermittent temporal slow waves in six (30%), and clinical signs pointing towards a focal seizure onset were found in seven patients (35%). Conclusion: Our study of EEG and clinical data supports the more sophisticated previous investigations in which structural and functional imaging as well as histopathological data suggested the presence of focal brain abnormalities in patients with ‘generalized’ epilepsies. Furthermore we emphasize the cautious use of isolated focal EEG abnormalities and certain clinical signs to prevent a premature diagnosis of focal epilepsy in patients who may indeed suffer from a generalized seizure disorder.     

Evoked electrospinogram in spinal cord and peripheral nerve disorders

Spinal cord evoked potentials have been studied by means of intrathecal application in 80 patients with various spinal cord and peripheral nerve disorders.
The segmental spinal cord potentials are normal in acute motor polyneuropathy, generalized anterior horn cell disease and in discrete lesions of dorso-lumbar segments. On the other hand, the first component of the segmental response is delayed, reduced and sometimes dispersed or lost in chronic sensory-motor polyneuropathy and in hereditary spinocerebellar degeneration. the reduction in amplitude is also present in multiple sclerosis with clinical signs of dorsal funiculus involvement.
In compressive lesions of the cauda-conus, recordings of lower thoracic intervertebral level show that the segmental responses are delayed with marked amplitude reduction.
The potentials recorded from lumbo-sacral segments show a greater the amplitude of the second component proportionally to the first one as the duration of second component is longer in spastic paraplegia regardless of its etiology.
The cervical tractus response is seen to be markedly slowed with a reduction of amplitude or is often absent in chronic polyneuropathy, spinocerebellar degeneration and in multiple sclerosis.
The primary sensory neurones lying both in periphery and in the dorsal column are assumed to be responsible for the segmental evoked potentials especially for the first component. the late slow component is related to the activation of interneurones situated within the segmental gray matter and segmental collaterals of the dorsal root fibres carrying impulses to those cells. Cervical tractus responses are mostly formed by the dorsal column fibres and their physiological action upon demyelination is similar to that of the peripheral nerves.     

Neuromodulation: spinal cord and peripheral nerve stimulation

Spinal cord and peripheral nerve stimulation for relief of chronic intractable pain have been used since the mid-1960s. Multiple mechanisms of action have been theorized without a clear-cut winner. The early frustrations with patient selection criteria and equipment difficulties have diminished secondary to carefully controlled studies and improvements in equipment designs. Efficacy studies consistently show an overall 50% improvement in long-term pain control in patients who have failed conservative or other invasive modalities. With improvements in today's technology, one hopes that better analgesia will be attainable.     

Focal cortical dysfunction and blood-brain barrier disruption in patients with Postconcussion syndrome.

Postconcussion syndrome (PCS) refers to symptoms and signs commonly occurring after mild head injury. The pathogenesis of PCS is unknown. The authors quantitatively analyzed EEG recordings, localized brain sources for abnormal activity, and correlated it with imaging studies. Data from 17 patients with neurologic symptomatology consistent with ICD-10 criteria for PCS was analyzed. Normalized quantitative EEG (QEEG) revealed significantly higher power in the delta band and lower power in the alpha band compared with matched controls. The generators for the abnormal rhythms were focally localized in neocortical regions. Brain computerized tomography and/or MRI did not reveal focal abnormality at the time of diagnosis. Single photon emission computed tomography (SPECT) after 99mTc-ethylcysteinate dimer administration showed a focal reduction in perfusion in 85% (n = 11) of the patients, and abnormal blood-brain barrier (BBB) after 99mTc-diethylenetriaminepentaacetic acid administration in 73% (n = 8). In 75% of these patients, low-resolution brain electromagnetic tomography analysis showed that the generators for abnormal rhythms were closely related to the anatomic location of the BBB lesion. These data point to focal cortical dysfunction in conjunction with BBB disruption and hypoperfusion as a possible mechanism of pathogenesis in at least some PCS patients, and offer QEEG and SPECT as important tools in evaluating these patients.     

Hyperventilation during orthostatic challenge in spinal cord-injured humans

Objective  

To determine whether arterial hypotension is related to hyperventilation during standing in individuals with complete spinal cord injury (SCI).     

Hypoventilation during passive leg movement in spinal cord-injured humans

We examined ventilatory response during passive walking-like exercise in the standing posture in complete spinal cord-injured humans and found that ventilatory equivalent for O₂ uptake, which would be related to the sensation of breathlessness, was lower during passive exercise than during quiet standing.     

Electrophysiological signs of peripheral nerve dysfunction in progressive myoclonus epilepsy

Electrophysiological findings were analysed in a group of 24 patients with progressive myoclonus epilepsy (PME) without Lafora bodies. Denervation activity in needle EMG and diminution of motor and sensory responses pointed out a mild axonal degeneration. We observed a significant slowing of motor and sensory conduction velocities in all the limb nerves examined, but distal motor latencies were not significantly increased. H-reflex latency of the posterior tibial nerve was prolonged. These results yielded the suggestion that there is a systemic peripheral nerve membrane dysfunction in PME.     

Subacute combined degeneration of spinal cord. Significance of peripheral nerve involvement

A 36 year old woman was admitted to the hospital in November 1983 because of her inability to walk. For 3 months prior to admission, she took oral contraceptives (OCs) as a treatment for amenorrhea. 2 months prior to admission, she had general malaise, anorexia, and unsteady gait. 1 month before her admission, tingling and numbness began in the fingertips and spread up to the forearms, a tight feeling around the waist developed, and walking became ataxic. On admission to the hospital, she was thin and pale with greying hair. Her mind was clear and there were no abnormalities of the cranial nerves. Her extremities were hypotonic but not wasted. Slight muscle weakness of the hands and feet was noted. There was myokymia in both legs. Deep tendon reflexes of the extremities were absent. The plantar responses were extensor and lack of coordination in the extremities was noted. There was a definite glove and stocking type of hypesthesia to pinprick and cotton wool. Vibration sense was decreased below T11 and lost in both legs. There was a marked loss of position sense to passive movement in the legs and some impairment in the hands. Laboratory examination revealed mild magaloblastic anemia, elevated LDH, borderline low concentration of vitamin B12 in the serum, increased excretion of methylmalonate in the urine, achylia, positive antiparietal cell antibody and positive anti-intrinsic factor antibody. Cyanocobalamin absorption by the Schilling test was 5.6% after intrinsic factor, 11.3%. The diagnosis of pernicious anemia was made. Upper gastrointestinal studies showed typical carcinoid tumors of the stomach. Cerebrospinal fluid was normal. Peripheral nerve conduction studies demonstrated normal or slightly decreased motor conduction velocities and absent sensory action potential. Sural nerve biopsy was performed. Myelinated fibers were moderately decreased in number to 5554/mm squared and pronounced loss of large myelinated fibers was demonstrated in fiber histogram. Teased method of the single fiber showed mainly axonal degeneration. Anemia and neurologic function improved rapidly with parenteral hydroxocobalamin therapy and 1 month after treatment commenced, she was able to walk without assistance. The clinical significance of peripheral nerve involvement of subacute combined degeneration of the spinal cord was discussed, as the peripheral nerve affection is only poorly understood in contrast to the myelopathy. This was followed by discussion of the possible effect of the OCs and gastric carcinoid to neurological manifestation of pernicious anemia. (author's modified)     

Anaesthesia of the spinal cord-injured patient: cardiovascular problems and their management.

An increased venous capacity and a decreased myocardial contractility can be expected in patients with an acute spinal cord lesion at or above T6. Both factors may contribute to a high incidence of arterial hypotension and pulmonary oedema in these patients especially during anaesthesia. We feel that the Swan-Ganz catheter provides valuable information concerning prevention, diagnosis and treatment of arterial hypotension and pulmonary oedema. Although there may be occasional difficulty in interpretation of measurements from the Swan-Ganz catheter if high airway pressures are used, it is a more sensitive monitor than C.V.P. measurement and is particularly useful in patients with a sympathectomy secondary to spinal cord trauma.     

X-irradiation of the contusion site improves locomotor and histological outcomes in spinal cord-injured rats.

We have determined whether X-irradiation of the injury site can oppose tissue loss and improve recovery of locomotor function following contusion injury of the spinal cord. Contusion injury was produced in rats at the level of T10 with a weight drop device. Localized X-irradiation (20 Gy) of the injury site was performed at 20 min and 1, 2, 4, 7, and 17 days postinjury. Locomotor recovery was then determined with the 21-point Basso, Beattie, and Bresnahan (BBB) scale. X-irradiation enhanced recovery of locomotor function during a subsequent 6-week observation period when administered 20 min and 1 or 2 days following contusion injury (final BBB score approximately 7-8). X-irradiation at 4-17 days postinjury did not significantly affect final locomotor scores compared with unirradiated rats (final BBB score approximately 2), in marked contrast to previous studies where X-irradiation applied only at 17-18 days benefitted transection injury. The extent of recovery was directly related to measurements of sparing of spinal cord tissue at the contusion center. Because the treatment time window occurred earlier in contusion than reported for transection injury, the results suggest that contusion injury rapidly initiates underlying radiation-sensitive processes that occur only following a delay of several weeks after transection injury. Further optimization of X-ray treatment may lead to a useful therapeutic modality for use in spinal cord contusion injury.     

Repetitive electrical stimulation of peripheral nerve and spinal cord activity

Spinal cord neuron and dorsal column fiber responses to electrical stimulation of the sciatic nerve in anesthetized cats were recorded before, during, and after periods of repetitive electrical stimulation of the sciatic nerve through an implantable nerve cuff stimulator device of the type and method used in human patients for pain relief. In previous publications from this laboratory using similar experimental conditions, we reported that repetitive electrical stimulation of the peripheral nerve suppressed all components of the compound action potential of nerves. The present study confirms that 5 percent of the spinal cord units studied showed facilitated discharge, 46 percent showed inhibited or depressed discharge, 36 percent underwent no change, and 13 percent showed equivocal responses to repetitive electrical stimulation. Inhibition of dorsal column fiber activity following repetitive electrical stimulation of peripheral nerve is not consistent with the Melzack-Wall gate hypothesis in which suppression of small fiber nociceptive input is mediated by large fiber activity. Our work suggests that the most commonly observed effect of electroanalgesia is to cause a more diffuse depression of nociceptive as well as nonnociceptive spinal cord activity.     

Regeneration in peripheral nerve grafts to the cat spinal cord

Peripheral nervous system grafts have long been known to promote CNS axonal elongation in the rodent. To investigate whether these principles also apply to a higher order animal, more suitable for physiologic studies, we performed autogenous sciatic nerve grafts to the adult cat spinal cord. This report is a brief, initial study of these grafts. In an effort to study both descending and ascending fibers as separately as possible, laminectomies were performed at both thoracic (T2-T9) and lumbar (L2-L4) levels. Aspiration lesions were made in the left side of the cord and the sciatic grafts were introduced. Three cats were studied with standard histological techniques, confirming previous reports of glial scar formation, collagen deposition, and cyst formation at the graft-CNS junction. In 7 other animals, at 146-179 days after the initial operation, the axonal origins were traced retrogradely using horseradish peroxidase and the tetramethyl benzidine technique. Reinnervation of the graft was found by intrinsic spinal cord neurons and dorsal root ganglia neurons. The number of reinnervating neurons was found to be greater than previously reported in the rodent. There was, however, no evidence of regeneration from brainstem nuclei when the grafts were placed at spinal levels where this has been seen in the rat. This may support an absolute maximum for regenerative distances vs a relative one. Although the amount of data was limited, it did support previous reports that peripheral axotomy enhances the regenerative response seen in primary sensory neurons.