Generalized Seizure Activity in an Adult Rhesus Macaque (Macaca mulatta) during Ketamine Anesthesia and Urodynamic Studies

We report a case of a generalized seizure in an adult female rhesus macaque (Macaca mulatta) undergoing a urodynamic evaluation while she was anesthetized with continuous-infusion ketamine. The seizure presented with generalized tonic–clonic activity during bladder infusion with saline. The tonic–clonic phase was self-limited and was followed by focal facial twitching, which was interrupted by bolus administration of intravenous diazepam. The ictal event was documented as pressure oscillations during cystometrogram recordings and a period of external urethral sphincter muscle activation, which was detectable by electromyography. An acute decrease in urethral pressure was demonstrated at the end of the generalized seizures. Ketamine anesthesia combined with relatively rapid infusion of saline into the bladder may have contributed to the onset of seizures. In addition, this case highlights the value of having a fast-acting benzodiazepine agent available to stop continuous or residual seizure activity during diagnostic or experimental procedures in anesthetized nonhuman primates.Anesthetic agents are used to sedate and immobilize nonhuman primates for veterinary health care and experimental studies. For these purposes, ketamine, a dissociative general anesthetic, is the agent used most commonly in macaques. Several protocols have been developed for the safe administration of ketamine, either as a single agent or as part of a balanced anesthetic approach administered orally, per rectum, intramuscularly, or intravascularly.^9,16,18 Although ketamine and other anesthetic agents are known to suppress physiologic responses during experimental studies, reflexive micturition may still be evoked, as demonstrated by urodynamic recordings in anesthetized rats.^1,2,10 In addition, urodynamic studies have demonstrated that bladder reflexes are suppressed by anesthesia in nonhuman primates, although comparative studies on the effects of different anesthetic agents have suggested that ketamine may be a suitable anesthetic for cystometrograms in rhesus macaques.⁵Here, parenteral administration of ketamine was used to sedate and immobilize adult rhesus macaques for comprehensive urodynamic studies. In one subject, the infusion of saline into the urinary bladder was associated with the acute onset of a generalized seizure, characterized by a self-limited period of tonic–clonic activity, followed by focal facial twitching, which was relieved by prompt intravenous administration of diazepam, and voiding. The tonic–clonic phase of the event was documented by cystometrography and electromyography recordings. We suggest the administration of ketamine anesthesia and the relatively rapid infusion of saline into the bladder as possible factors that may have contributed to the ictal event in this rare case of a clinical seizure during a urodynamic study in a nonhuman primate.     

Generalized convulsive seizures are associated with ketamine anesthesia in a rhesus macaque (Macaca mulatta) undergoing urodynamic studies and transcutaneous spinal cord stimulation

A female rhesus macaque developed two episodes of generalized convulsions during transcutaneous spinal cord stimulation (TSCS) and urodynamic studies under ketamine anesthesia. The seizures took place in the absence of active TSCS and bladder pressure elevation. Ketamine anesthesia remains the primary risk factor for the convulsions during these experimental procedures.     

Neurofilamentous hypertrophy of intramedullary axonal arbors in intact spinal motoneurons undergoing peripheral sprouting

An incomplete motor nerve injury or a partial loss of motoneurons leads to a partial denervation of skeletal muscle. As part of a compensatory response, the remaining intact motoneurons undergo peripheral sprouting and increase their motor unit size. Our knowledge about the responses in the more proximal parts of these sprouting motoneurons is sparse, however. We investigated the effects of an incomplete transection of the medial gastrocnemius (MG) nerve in the adult cat on the morphology of the intramedullary axon and axon collateral systems of the remaining intact MG motoneurons. At twelve weeks following the partial transection of the MG nerve, intracellular recording and labeling techniques were used to deposit horseradish peroxidase into single intact MG motoneurons for detailed morphological studies. The light microscopic appearance and caliber of the intramedullary stem motor axons of the intact MG motoneurons were indistinguishable from controls. The number and size of the intramedullary motoraxon collateral systems were also unchanged. However, frequent and marked hypertrophy of the distal portions of the motoraxon collaterals was encountered. Electron microscopic studies of the hypertrophied collaterals demonstrated abnormal accumulations of disorganized neurofilaments arranged in bundles or whorls. The morphological changes were indistinguishable from the neurofilamentous hypertrophy that has previously been reported in Wallerian degeneration, in experimental and human motor neuron disease and in some regenerating axonal processes of spinal motoneurons. We conclude that, neurofilamentous hypertrophy of the intramedullary arbors of motor axons may also be part of a reactive and non-degenerative response in intact motoneurons undergoing compensatory peripheral sprouting.     

Modulation of the visceromotor reflex by a lumbosacral ventral root avulsion injury and repair in rats

Increased abdominal muscle wall activity may be part of a visceromotor reflex (VMR) response to noxious stimulation of the bladder. However, information is sparse regarding the effects of cauda equina injuries on the VMR in experimental models. We studied the effects of a unilateral L6-S1 ventral root avulsion (VRA) injury and acute ventral root reimplantation (VRI) into the spinal cord on micturition reflexes and electromyographic activity of the abdominal wall in rats. Cystometrogram (CMG) and electromyography (EMG) of the abdominal external oblique muscle (EOM) were performed. All rats demonstrated EMG activity of the EOM associated with reflex bladder contractions. At 1 wk after VRA and VRI, the duration of the EOM EMG activity associated with reflex voiding was significantly prolonged compared with age-matched sham rats. However, at 3 wk postoperatively, the duration of the EOM responses remained increased in the VRA series but had normalized in the VRI group. The EOM EMG duration was normalized for both VRA and VRI groups at 8-12 wk postoperatively. CMG recordings show increased contraction duration at 1 and 3 wk postoperatively for the VRA series, whereas the contraction duration was only increased at 1 wk postoperatively for the VRI series. Our studies suggest that a unilateral lumbosacral VRA injury results in a prolonged VMR to bladder filling using a physiological saline solution. An acute root replantation decreased the VMR induced by VRA injury and provides earlier sensory recovery.     

Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse

Congenitally hypomyelinated shiverer mice fail to generate compact myelin and die by 18-21 weeks of age. Using multifocal anterior and posterior fossa delivery of sorted fetal human glial progenitor cells into neonatal shiverer x rag2(-/-) mice, we achieved whole neuraxis myelination of the engrafted hosts, which in a significant fraction of cases rescued this otherwise lethal phenotype. The transplanted mice exhibited greatly prolonged survival with progressive resolution of their neurological deficits. Substantial myelination in multiple regions was accompanied by the acquisition of normal nodes of Ranvier and transcallosal conduction velocities, ultrastructurally normal and complete myelination of most axons, and a restoration of a substantially normal neurological phenotype. Notably, the resultant mice were cerebral chimeras, with murine gray matter but a predominantly human white matter glial composition. These data demonstrate that the neonatal transplantation of human glial progenitor cells can effectively treat disorders of congenital and perinatal hypomyelination.