Diaphragm remodeling and compensatory respiratory mechanics in a canine model of Duchenne muscular dystrophy.

Ventilatory insufficiency remains the leading cause of death and late stage morbidity in Duchenne muscular dystrophy (DMD). To address critical gaps in our knowledge of the pathobiology of respiratory functional decline, we used an integrative approach to study respiratory mechanics in a translational model of DMD. In studies of individual dogs with the Golden Retriever muscular dystrophy (GRMD) mutation, we found evidence of rapidly progressive loss of ventilatory capacity in association with dramatic morphometric remodeling of the diaphragm. Within the first year of life, the mechanics of breathing at rest, and especially during pharmacological stimulation of respiratory control pathways in the carotid bodies, shift such that the primary role of the diaphragm becomes the passive elastic storage of energy transferred from abdominal wall muscles, thereby permitting the expiratory musculature to share in the generation of inspiratory pressure and flow. In the diaphragm, this physiological shift is associated with the loss of sarcomeres in series (∼ 60%) and an increase in muscle stiffness (∼ 900%) compared with those of the nondystrophic diaphragm, as studied during perfusion ex vivo. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of respiratory failure in DMD.

Functional muscle analysis of the Tcap knockout mouse.

Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.

Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I-IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. RESULTS: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). RECOMMENDATIONS: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Myofiber injury and regeneration in a canine homologue of Duchenne muscular dystrophy.

OBJECTIVE: To test the hypothesis that differential skeletal muscle involvement, previously observed in dogs with a homologue of Duchenne muscular dystrophy, correlates with the histochemical markers of myofiber injury and regeneration. DESIGN: Evidence of injury (cellular penetration by Evans blue dye, immunoglobulin G expression, hematoxylin and eosin staining of necrotic figures), myofiber regeneration (fetal myosin heavy chain isoform expression), and morphologic indices in the cranial sartorius (CS), long digital extensor, and vastus lateralis muscles were examined in five dogs with dystrophy and five normal dogs. RESULTS: Only the CS muscle, at 1 mo, demonstrated significant differences in injury when compared with age-matched controls. By 6 mo, the long digital extensor and vastus lateralis also suffered greater than normal injury. Only the dystrophic CS tissue expressed a notable increase in mean myofiber diameter when compared with other muscles at 6 mo. Normal CS muscles revealed a distinct population of small myofibers at this age. CONCLUSION: The CS seems unique in its selective pathologic involvement. These differences may contribute to the marked regenerative response of this muscle in the dystrophic state. An improved understanding of mechanisms by which some dystrophin-deficient canine muscles remain spared from injury may provide clues to investigate and prevent the degenerative processes in humans.

Contraction force generated by tarsal joint flexion and extension in dogs with golden retriever muscular dystrophy.

Force generated due to torque caused by tarsal joint flexion and extension was measured noninvasively at 3, 4.5, 6, and 12 months of age in dogs with the Duchenne homologue, golden retriever muscular dystrophy (GRMD). Absolute and body-weight-corrected GRMD twitch and tetanic force values were lower than normal at all ages (P<0.01 for most). Tarsal flexion and extension were differentially affected. Flexion values were especially low at 3 months, whereas extension was affected more at later ages. Several other GRMD findings differed from normal. The twitch/tetany ratio was generally lower; post-tetanic potentiation for flexion values was less marked; and extension relaxation and contraction times were longer. The consistency of GRMD values was studied to determine which measurements will be most useful in evaluating treatment outcome. Standard deviation was proportionally greater for GRMD versus normal recordings. More consistent values were seen for tetany versus twitch and for flexion versus extension. Left and right limb tetanic flexion values did not differ in GRMD; extension values were more variable. These results suggest that measurement of tarsal tetanic force should be most useful to document therapeutic benefit in GRMD dogs.

Inhibitory casting decreases a vibratory inhibition index of the H-reflex in the spastic upper limb.

OBJECTIVE: To test the hypothesis that application of an inhibitory cast to the spastic upper limb will decrease a vibratory inhibition index (VII) of the H-reflex in the spastic upper limb. DESIGN: Prospective, nonrandomized, open-label trial. SETTING: University tertiary care center. PARTICIPANTS: Eight adults with upper limb spasticity. INTERVENTION: Fiberglass cast application spanning the wrist to the upper arm. MAIN OUTCOME MEASURE: The amplitude of the H-reflex with and without continuous 60Hz vibration to the tendon of the flexor carpi radialis was measured, and the VII was calculated using the formula: [H-reflex amplitude (vibrated)/H-reflex amplitude (control)] x 100%. RESULTS: Mean VII decreased from baseline (70.7) on day 1 (67.6, p = .699), day 2 (55.9, p =.066), and day 3 (43.5, p = .033) of casting, and increased on day 4 (89.9, p = .146) after removal of the cast. CONCLUSION: Findings lend support to the idea that during application of an inhibitory cast motor neuron excitability is decreased in the spastic upper limb.

Selective serotonin reuptake inhibitor treatment of post-traumatic Klüver-Bucy syndrome.

Two cases of Klüver-Bucy syndrome following severe traumatic brain injury (TBI), are described during the period of recovery from acute TBI. These patients posed significant management problems, until successfully managed with selective serotonin reuptake inhibitors (SSRIs). These cases support the benefit of SSRIs in treating associated Klüver-Bucy syndrome.

The effects of normal ageing on neuropsychological functioning following traumatic brain injury.

Increasing age is associated with greater absolute neuropsychological impairment (e.g. slower processing speed, diminished memory), although it is unclear if older individuals with traumatic brain injury (TBI) show greater relative impairment than younger individuals with TBI. The current study evaluated the effects of normal ageing on TBI by using age-based normative data to calculate indices of relative decline from pre-morbid levels (expressed as z-deficit scores) for different age groups (20-39 years, 40-59 years, 60+ years). The sample included 279 individuals with TBI between the ages of 20 and 65 who were assessed in a department of rehabilitation neuropsychology laboratory over a 4-year period. Spearman correlations and ANOVAs did not show age-related differences in relative memory, attention or speed of processing abilities, although results did indicate that increasing age is associated with relatively less impairment in intelligence. The results suggest that the greater neuropsychological impairment noted in older individuals with TBI is most likely related to normal ageing. The importance of considering both absolute and relative degrees of impairment is discussed.

Obsessional disorders during recovery from severe head injury: report of four cases.

Four cases of transient obsessional disorders following severe head injury are described within the context of recovery from acute traumatic brain injury (TBI). Obsessional features following TBI have important treatment implications in brain injury rehabilitation settings, since emergence of this disorder in the acutely brain injured patient poses a significant obstacle to interdisciplinary rehabilitation. Although the numbers of patients described here and in previous reports are too small to draw conclusions about the incidence of obsessional disorders following TBI, these cases illustrate the importance of correctly identifying and treating obsessional symptoms in the brain injured patient.

Assessment of neuroendocrine dysfunction following traumatic brain injury.

Posttraumatic neuroendocrine pathology may be a clinically significant complication following traumatic brain injury (TBI). Metabolic abnormalities are described after TBI in two cases. A 21 year old male injured in a motor vehicle accident admitted in a minimally responsive condition presented with fluctuating high sodium levels, undetectable serum testosterone, and depressed cortisol and thyroid function. Imaging revealed near complete avulsion of the pituitary stalk leading to panhypopituitarism. A 38 year old male admitted for occipital skull fractures and brain contusions presented with hyponatremia and low serum testosterone. Both patients required hormonal replacement and correction of electrolyte abnormalities. A screening protocol adapted for selected patients at risk for endocrine problems is described. While neuroendocrine screening is not advocated in all TBI patients, physicians should be aware of the importance of neuroendocrine dysfunction following TBI.

Evaluating motor end-plate-targeted injections of botulinum toxin type A in a canine model.

Tarsal joint forces were measured in dogs over 70 days following botulinum toxin type A (BTX-A) injections. Three dogs were injected at motor end-plates located by electromyography (EMG), while 3 dogs were similarly injected, but without EMG guidance. Extension forces were significantly (P < 0.05) smaller in limbs injected at motor end-plates than in corresponding limbs on days 14 and 35. There were no significant differences at other times. Using these techniques, EMG end-plate targeting potentiates effects of BTX-A.

Assessment of neuroendocrine dysfunction following traumatic brain injury.

Posttraumatic neuroendocrine pathology may be a clinically significant complication following traumatic brain injury TBI. Metabolic abnormalities are described after TBI in two cases. A 21 year old male injured in a motor vehicle accident admitted in a minimally responsive condition presented with fluctuating high sodium levels, undetectable serum testosterone, and depressed cortisol and thyroid function. Imaging revealed near complete avulsion of the pituitary stalk leading to panhypopituitarism. A 38 year old male admitted for occipital skull fractures and brain contusions presented with hypona tremia and low serum testosterone. Both patients required hormonal replacement and correction of electrolyte abnormalities. A screening protocol adapted for selected patients at risk for endocrine problems is described. While neuroendocrine screening is not advocated in all TBI patients, physicians should be aware of the importance of neuroendocrine dysfunction following TBI.

Use of carbidopa-levodopa in a patient with hydrocephalus and frozen movement.

While movement disorders are frequently encountered after brain injuries, and may create a host of complicated problems for the clinician, only a few cases of Parkinsonism associated with hydrocephalus have ever been described in the literature. Parkinsonism-like syndrome complicating hydrocephalus is a rare disorder, especially when associated with nontumoral aqueductal stenosis. Yet as this case report discusses, hdyrocephalus-induced Parkinsonism may be responsive to levodopa-carbidopa administration. This report describes a perplexing case of persistent akinesis following corrective surgery for aqueductal stenosis and the subsequent response to levodopa-carbidopa administration. We present the case of a 28-year-old male with a history of non-tumoral aqueductal stenosis diagnosed at age 12. As a child, he underwent a ventriculo-peritoneal shunt placement for obstructive hydrocephalus followed by multiple shunt revisions over the next several years. Sixteen years after his initial shunt placement, the patient presented with a decline in mental status. A third ventriculocisternostomy was performed rather than another shunt revision. Following surgery, the patient remained obtunded, and displayed profound hypokinesis, best described as freezing in movement. Upon admission to a rehabilitation unit 2 weeks later, he had made only minimal progress. A SPECT (single-photon emission computed tomography) brain scan revealed decreased basal ganglia perfusion. Levodopa/carbidopa therapy was initiated and within 2 weeks, the patient showed improvement in speed of movement, facial expression and verbal output. Eight weeks later, the patient could independently complete his basic activities of daily living and demonstrated little, if any, disordered movement. This report illustrates how dopaminergic agents may be useful in cases of hypokinesis following corrective surgery for aqueductal stenosis. SPECT may further aid in the diagnosis and management of Parkinsonism-like syndromes in brain injuries.

Lumbar spinal moments in chronic back pain patients during supported lifting: a dynamic analysis.

OBJECTIVES: The main objective of this study was to test the hypothesis that peak L4/L5 moments (torque) placed on the lumbar spine by chronic back pain subjects are reduced using pain-reducing postural adaptations. A secondary objective was to determine the relation between lumbar moments while lifting and self-reported ratings of lower back pain. STUDY DESIGN: Cohort using seven men with a history of chronic lower back pain. An inverse dynamic model was used to calculate L4/L5 forces and moments while performing five trials each of two lifting styles. Subjective ratings of lumbar back pain were taken before and after the lifts. RESULTS: Significant (p < .001) differences were found between lifting postures on peak L4/L5 net reaction moments. Two distinct lifting profiles emerged characterized by the amount of lumbar spinal extensor musculature involved. Significant (p < .05) increases in pain were found after a bowed-back lifting style. CONCLUSIONS: Peak L4/L5 net reaction moments were less (spine extensor loading) for a lifting posture that produced lower levels of self-reported lower back pain. The dynamic model proved reliable and useful for future study of the pathomechanics of lower back pain.

Psychomotor agitation following gabapentin use in brain injury.

Gabapentin, an anticonvulsant structurally related to gamma-aminobutyric acid (GABA) was recently reported to be effective in pain associated with reflex sympathetic dystrophy (RSD) and in pain associated with neuropathy. Yet, to our knowledge, the use of gabapentin for neuropathic pain in the presence of cognitive impairment has not been reported. In this report, we describe two patients (one with a traumatic brain injury, one with a putative acquired brain injury) who presented to a neurorehabilitation unit complaining of pain that was diagnosed as neurologically mediated. Within one week of receiving a daily 900 mg dose of gabapentin, both patients complained of heightened anxiety and restlessness. Correspondingly, each reported a diminution of psychological symptoms within 48 hours of gabapentin cessation. These two cases suggest that gabapentin may cause agitation in cognitive impaired patients. Physicians treating brain-injured patients and prescribing gabapentin for neuropathic pain may wish to closely monitor patients for similar signs of restlessness or anxiety.

Kinematic changes following botulinum toxin injection after traumatic brain injury.

The objectives of this study were to: (1) demonstrate the use of computerized, three-dimensional gait analysis as a functional assessment instrument following clinical intervention; and (2) objectively quantify the effects of focal muscle denervation via botulinum toxin type A (BTXA) injection in a hemiparetic patient with lower extremity spasticity following traumatic brain injury (TBI). A desired outcome of this intervention was to realize kinematics more closely resembling those reported for normal patients. The design was a single-subject case study. Ten trials of walking gait were analysed pre-injection (PI), 1 week post-injection (1PO) and 4 weeks post-injection (4PO). The PI and 1PO sessions were found to be appreciably different from the 4PO on the joint angles of the ankle and knee at each phase of the gait cycle. These differences resulted in a reduced asymmetry of ambulation. Stride time, stance time, percentage stance time, percentage swing time and walking speed improved, showing progress towards a more efficient gait pattern. Decreased stride time and increased walking speed supported improved functional ability. The inter-trial variability of the gait parameters showed the analysis to be a consistently reproducible protocol. Conclusions based on the results included encouraging findings for the efficacy of botulinum toxin A as a therapy for the reduction of spasticity.

Common patterns of clinical motor dysfunction.

An upper motor neuron syndrome often leads to the development of stereotypical patterns of deformity secondary to agonist muscle weakness, antagonist muscle spasticity and changes in the rheologic (stiffness) properties of spastic muscles. Identification of the spastic muscles that contribute to deformity across a joint allows therapeutic denervation to be implemented with the maximum likelihood of success. Identifying responsible muscles can be complex, since many muscles may cross the joint involved, and not all muscles with the potential to cause deformity will be spastic. Strategies including polyelectromyography and diagnostic blocks with local anesthetics can be used to test hypotheses regarding the deformity, providing information for more long-term denervation. In this review, we discuss frequently observed patterns of deformity associated with problematic spasticity, paresis, contracture, and impaired voluntary motor control.

Comparison of two injection techniques using botulinum toxin in spastic hemiplegia.

This study sought to test the hypothesis that injections of botulinum toxin type A (BTX-A) at the mid belly of the gastrocnemius muscle in spastic hemiplegic adults produce superior clinical results to proximal injections directed toward the muscular origin. We designed a randomized, double-blind, placebo-controlled intervention study at a university tertiary care setting. Seventeen subjects with chronic spastic hemiplegic gait were enrolled from a volunteer community sample; time range from acute neurologic insult was 0.75 to 31 yr; age range was 19 to 71 yr; gender consisted of 11 men and 4 women; diagnoses were 12 patients with stroke, 2 with traumatic brain injuries, and 1 with a brain tumor. Two subjects were withdrawn from the study because of (1) acute vascular occlusion before intervention and (2) noncompliance with follow-up visits. After baseline measurements, subjects were injected with 50 units of BTX-A (volume, 0.5 cc) into the medial or lateral gastrocnemius: (1) proximally at one site near the muscular origin; (2) distally at three sites along the mid belly. We measured outcome using the Fugl-Meyer score, Ashworth scale, ankle range of motion, and a timed 50-ft fastest walk. No outcome measures showed a significant effect attributable to site of injections. Confounding variables included physical therapy and varying duration of illness in the study cohort. We conclude that the results failed to support the hypothesis that BTX-A injections at the mid belly of the gastrocnemius produced superior functional improvements to injections located near the muscular origin using localization techniques described. Additional research comparing more precise localization methods for BTX-A injections might further establish the importance of electromyographic guidance using BTX-A in management of spasticity.

Post-traumatic hyperthermia in acute brain injury rehabilitation.

Fever frequently presents during recovery from traumatic brain injury (TBI). Elevated body temperature may result from ensuing infection, thrombophlebitis, drug reaction, or a defect in the central thermoregulatory system such as seen in post-traumatic hyperthermia (PTH). Typically, the diagnosis of PTH follows only after thorough investigation. Literature supports the theory that the febrile TBI patient, lacking a documented source, has central hyperthermia. The purpose of this study was to determine the incidence of PTH in the acute rehabilitation setting. We reviewed a consecutive series of 84 TBI patients participating in a rehabilitation programme. Four per cent of the patients in this study met our criteria for PTH. We describe a fever protocol that should aid the physician in diagnosis and treatment of the febrile TBI patient. Proposed mechanisms involved in thermoregulation are discussed.