Jan K. Korthals

The Effect of Hyperglycemia on Nerve Conduction and Structure Is Age Dependent

The nerve conduction velocity (NCV) of nondiabetic male Wistar rats continues to increase until ∼ 26 weeks of age. Rats made hyperglycemic at 6 weeks of age manifest reduced NCV by 10 weeks of age and show morphological differences in the sciatic tibial nerve after 5 months of hyperglycemia when compared with age-matched controls. Fiber diameter, myelin width, and the number of large myelinated fibers were decreased in the tibial nerves of the hyperglycemic animals. Rats made hyperglycemic at 26 weeks of age had elevated glycosylated hemoglobin and sciatic nerve sorbitol levels but maintained normal NCVs and had little change in morphology after 7 months of hyperglycemia. Thus, animals with maturing peripheral nerve structure and function exposed to chronic hyperglycemia manifest greater pathological alterations than those that occur when more matured nerves are exposed to similarly elevated glucose concentrations for an even greater duration. We suggest that immature animal models commonly used to study diabetic peripheral neuropathy may not be appropriate for understanding a process that commonly develops in humans who become hyperglycemic after maturation of the peripheral nerves.

Nerve and muscle vulnerability to ischemia

Nerve and muscle vulnerability to structural damage during ischemia was examined in the hind legs of 50 cats after transient simultaneous clamping of the aorta and femoral artery for 1 to 10 h. Not until 5 h of ischemia were mild necrotic changes noted in nerves. Moderate to severe changes occurred after 8 h of ischemia. Contrariwise, mild muscle necrotic changes developed after 2-3 h, and moderate to severe changes after 5-7 h. The anterior tibialis muscle was usually more severely damaged than the gastrocnemius and soleus muscles. These studies demonstrate that: Longer periods of ischemia are required to produce nerve damage than suggested by previous tourniquet compression experiments. Longer periods of ischemia are necessary to produce necrosis in the posterior than anterior and lateral compartment muscles of the leg. Muscle is more vulnerable than nerve to ischemia.

Diffuse Axonal Injury Without Direct Head Trauma and With Delayed Onset of Coma

A 16-year-old female was involved in a jet ski (water craft) accident resulting in bilateral lower extremity fractures but no loss of consciousness or any other evidence of head trauma. Thirty hours later she became comatose. Magnetic resonance imaging was consistent with diffuse axonal injury. She recovered after several weeks without any clinical sequelae. This patient demonstrates an unusual example of diffuse axonal injury without direct head trauma and with delayed onset of symptoms. The authors recommend that patients involved in high-velocity accidents, even without immediate evidence of head injury, be observed for signs of diffuse axonal injury.

Progressive Necrotizing Myelopathy Associated With Leukemia: Clinical, Pathologic, and MRI Correlation

We describe a patient with progressive, irreversible, necrotizing myelopathy associated with myelomonocytic leukemia. The neuropathologic lesions consisted of diffuse necrosis, most pronounced in the cervical cord and affecting both the gray and white matter. These areas corresponded to areas of increased T2 on magnetic resonance imaging scans of the patient. We felt that there was no causal relationship of these lesions to any single antileukemic agent the patient received, and no other local or systemic causes were found to explain the lesions at necropsy. It is suggested that our case is an example of paraneoplastic necrotizing myelopathy. To our knowledge, this is the third case of necrotizing myelopathy associated with leukemia reported in the English medical literature, and the first one demonstrating usefulness of magnetic resonance imaging in diagnosis of necrotizing myelopathy. (J Child Neurol 1987;2:44-49).

Nerve regeneration patterns after acute ischemic injury

We performed morphologic studies on regeneration of the cats hind limb nerves, following simultaneous ligation of the aorta and right femoral artery. There were 2 regeneration patterns depending on the extent of ischemic necrosis. When nerve infarcts were limited only to intrafascicular regions, there was no basic change of nerve microarchitecture during regeneration. Extension of the necrosis to the perineurium resulted in replacement of the original fascicle by a collection of small fascicles, many of which were surrounded by their own perineurium. These mini fascicles formed within the boundaries of the old perineurium.

Distribution of nerve lesions in serotonin-induced acute ischemic neuropathy

SummaryWe have developed a new model of an acute ischemic nerve injury in rat produced by the combined effects of right femoral artery ligation and intraperitoneal injection of serotonin. Light microscopic studies were performed on the right sciatic, tibial, plantar and sural nerves dissected from rats 7 days to 6 months after serotonin injection. Ischemic lesions occurred mostly in the middle tibial nerve and involved either a part or the whole transverse nerve section. Partial tibial nerve lesions appeared mainly as small subperineurial or large wedge-shaped areas of fiber loss or regeneration. No well-deiineated central fascicular lesions were seen. Sural nerves were less damaged than tibial nerves. The predominantly subperineurial fascicular distribution of ischemic lesions seen in the present model differs from the central fascicular distribution found in previous experimental studies on nerve ischemia. The different distribution of lesions is probably related to the small fascicular size and local microvascular architecture of the affected nerve segment, as well as to the method of producing ischemia.

PROGRESSION OF REGENERATION AFTER NERVE INFARCTION

We performed morphologic studies on the progression of regeneration in cat hind limb nerves after acute ischemic injury. None of the damaged nerve trunks showed a major increase in endoneurial connective tissue. Despite this fact, regeneration of nerve with transfascicular infarct was far from complete even 16 months after injury as manifested by a striking increase in the small myelinated fibers (MF) number and decrease in large MF number. Restoration of infarcted nerves was less complete than that previously reported after a nerve crush. Changes in the necrotic nerve segment and difficulty in making target contact with muscle and other tissues damaged by ischemia may be limiting factors in the regeneration of infarcted nerves.

The effects of acetyl-L-carnitine and sorbinil on peripheral nerve structure, chemistry, and function in experimental diabetes.

Nerve conduction velocity (NCV) increased with age in nondiabetic male Wistar rats for the first 26 weeks of life. The NCV of animals made hyperglycemic at age 6 weeks by administration of streptozotocin (STZ) also increases, but at a slower rate. Animals with 4 weeks of hyperglycemia and reduced NCV treated with an aldose reductase inhibitor (sorbinil) or a short-chain acyl-carnitine (acetyl-L-carnitine [ALC]) daily for 16 weeks showed an improvement in NCV. Morphometric studies of tibial nerves collected from animals after 20 weeks of hyperglycemia (age 26 weeks) showed a consistent reduction in the width of the myelin sheath and little change in axon area. The number of large myelinated fibers (>6.5 microns) found in nerves collected from hyperglycemic animals was less than the number found in nondiabetic animals. Treatment of hyperglycemic rats with either sorbinil or ALC was associated with increased NCV, myelin width, and large myelinated fibers. The apparent metabolic effect of these agents was similar for fatty acid metabolism, but different for polyol pathway activity. We conclude that in animals hyperglycemic long enough to slow NCV, sorbinil and/or ALC treatment reduces the functional, structural, and biochemical changes associated with hyperglycemia that occur in the myelin sheath.

Carnitine palmityltransferase deficiency with permanent weakness

A 16-year-old male had a history of muscle pain and exercise intolerance from the age of six years. At 14 years of age, he experienced the first episode of myoglobinuria and has had eight episodes subsequently. The longest interval between episodes was 14 months. Between attacks he manifested permanent, mild proximal limb weakness, elevated serum creatine kinase activity, and myopathic features indicated by electromyography and muscle biopsies. The muscle carnitine palmityltransferase activity was 30% of normal. This patient demonstrates that carnitine palmityltransferase deficiency can be a progressive disorder leading to permanent weakness. The need for early diagnosis and treatment is stressed.

Improvement in peripheral nerve function after one year of Sorbinil

The effect of 250 mg day-1 of the aldose reductase inhibitor, Sorbinil, upon peripheral nerve function was assessed in 23 adult diabetics with clinical neuropathy. Sorbinil was given for 4 weeks to 10 subjects, while 13 received placebo in this double-blind study. Open label treatment with Sorbinil was then continued for 52 weeks in 10 of the 23 subjects. Red cell sorbitol, hemoglobin A1c, vibratory sensation, median nerve sensory and motor conduction velocities were measured at 0, 4 and 52 weeks. There were no measurable changes in peripheral nerve function after 4 weeks of Sorbinil treatment. After 52 weeks significant improvement was found in the median nerve motor and sensory conduction velocities. This was associated with no change in blood glucose control but a reduction of erythrocyte sorbitol levels.