Outcomes of Selective Arthrodesis Based on Joints Affected in 33 Feet With Müller-Weiss Disease.

No consensus exists regarding operative treatment of Müller-Weiss disease (MWD). Its only classification is based solely on Méary's angle and serves neither as guide to management nor prognosis. We report on 33 feet that underwent surgery following failed conservative management. Treatment was directed towards joint(s) involved, as determined by clinical examination, plain radiography and SPECT-CT. Thus, surgery consisted of isolated talonavicular in 6 feet, triple in 8, subtalar and talonavicular in 7, talonaviculocuneiform in 4, talonaviculocuneiform with interpositional tricortical iliac crest graft in 6 and pantalar arthrodesis in 2. PROMIS scores for pain interference and depression decreased significantly (p < .001) with significant accompanying increase in physical function (p = .003). Union occurred in 31 of 33 feet (94%) with complete resolution of pain at an average follow-up of 84 months. Of the 2 nonunions, 1 had fracture through the lateral navicular, and the other marked sclerosis and avascularity of the lateral navicular. We describe our pathways for selecting arthrodesis based on the joints affected. Isolated talonavicular arthrodesis was performed in early stages of MWD, which begins at the talonavicular articulation. When disease extended to both sides of the navicular, we performed talonaviculocuneiform arthrodesis. When considering isolated talonavicular, double medial or triple arthrodesis, there should be adequate cancellous bone stock remaining in the lateral part of the navicular, as determined on medial oblique radiographs and CT scan. In case of inadequate bone stock or fracture through the lateral navicular, talonaviculocuneiform arthrodesis with interpositional iliac crest bone graft is recommended.

Towards understanding Müller-Weiss disease from an analysis of 95 cases.

BACKGROUND: The single existing classification of Müller-Weiss Disease (MWD), based solely upon Méary's angle, serves neither as guide for prognosis nor treatment. This accounts for lack of gold standard in its management. METHODS: Navicular compression, medial extrusion, metatarsal lengths, Kite's, lateral and dorsoplantar talo-first metatarsal angles were measured in 95 feet with MWD. Joints involved, presence and location of navicular fracture were recorded. RESULTS: Group 1 "early-onset" MWD feet (n = 11) had greatest compression and medial extrusion, and lowest Kite's angles. All except 1 were index minus and had lateral navicular fracture. Only 1 had moderate degeneration at the talonavicular joint (TNJ) with none requiring surgery yet. Group 2 "Müller-Weissoid" feet (n = 23) had radiologically normal navicular in their fifties and developed MWD on average 5 years later. They had the lowest compression and extrusion, and highest Kite's angles. None had complete fracture. All had TNJ arthritis, with early changes at lateral naviculocuneiform joint (NCJ) in 43%. Group 3 "late-onset" MWD presented in the sixth decade. Only TNJ was involved in Group 3 A (n = 16). Group 3B (n = 20) affected TNJ more than NCJ and had the greatest number of Maceira stage V disease. Group 3 C "reverse Müller-Weiss disease", which affected NCJ more than TNJ (n = 25), had greatest midfoot abduction and overlength of the second metatarsal. No fracture occurred in group 3 A compared to 65% and 32% in groups 3B and 3 C, respectively. CONCLUSIONS: With need to compare like-for-like pathology, the proposed classification provides a common platform for reporting outcomes of different treatments. We theorize pathogenetic pathways in the various groups.

Atraumatic Pantalar Avascular Necrosis in a Patient With Alcohol Dependence.

In the United States, an estimated 10,000 to 20,000 new cases of avascular necrosis are diagnosed each year. We present an unusual case of atraumatic avascular necrosis with widespread hindfoot and midfoot involvement. A 62-year-old female with a history of alcohol dependence and smoking, who had previously been treated for avascular necrosis of the knee, presented with right-sided foot pain and difficulty weightbearing. Imaging studies revealed extensive avascular necrosis of the hindfoot and midfoot, which precluded simple surgical intervention. The patient was followed up for 18 months. In the last 8 months of the 18-month period, the patient managed her symptoms using an ankle-foot orthosis. A diagnosis of avascular necrosis should be considered in patients with atraumatic foot and ankle pain, especially in the presence of risk factors such as alcohol excess and smoking.

Enhanced neurotrophic distribution, cell signaling and neuroprotection following substantia nigral versus striatal delivery of AAV2-NRTN (CERE-120).

This paper reassesses the currently accepted viewpoint that targeting the terminal fields (i.e. striatum) of degenerating nigrostriatal dopamine neurons with neurotrophic factors in Parkinson's disease (PD) is sufficient for achieving an optimal neurotrophic response. Recent insight indicating that PD is an axonopathy characterized by axonal transport deficits prompted this effort. We tested whether a significantly greater neurotrophic response might be induced in SN neurons when the neurotrophic factor neurturin (NRTN) is also targeted to the substantia nigra (SN), compared to the more conventional, striatum-only target. While recognizing the importance of maintaining the integrity of nigrostriatal fibers and terminals (especially for achieving optimal function), we refocused attention to the fate of SN neurons. Under conditions of axonal degeneration and neuronal transport deficits, this component of the nigrostriatal system is most vulnerable to the lack of neurotrophic exposure following striatal-only delivery. Given the location of repair genes induced by neurotrophic factors, achieving adequate neurotrophic exposure to the SN neurons is essential for an optimal neurotrophic response, while the survival of these neurons is essential to the very survival of the fibers. Two separate studies were performed using the 6-OHDA model of nigrostriatal degeneration, in conjunction with delivery of the viral vector AAV2-NRTN (CERE-120) to continuously express NRTN to either striatum or nigra alone or combined striatal/nigral exposure, including conditions of ongoing axonopathy. These studies provide additional insight for reinterpreting past animal neurotrophic/6-OHDA studies conducted under conditions where axon transport deficiencies were generally not accounted for, which suggested that targeting the striatum was both necessary and sufficient. The current data demonstrate that delivering NRTN directly to the SN produces 1) expanded NRTN distribution within the terminal field and cell bodies of targeted nigrostriatal neurons, 2) enhanced intracellular neurotrophic factor signaling in the nigrostriatal neurons, and 3) produced greater numbers of surviving dopamine neurons against 6-OHDA-induced toxicity, particularly under the conditions of active axonopathy. Thus, these data provide empirical support that targeting the SN with neurotrophic factors (in addition to striatum) may help enhance the neurotrophic response in midbrain neurons, particularly under conditions of active neurodegeneration which occurs in PD patients.

Properly scaled and targeted AAV2-NRTN (neurturin) to the substantia nigra is safe, effective and causes no weight loss: support for nigral targeting in Parkinson's disease.

Recent analyses of autopsied brains from subjects previously administered AAV2-neurturin (NRTN) gene transfer argues that optimizing the effects of neurotrophic factors in Parkinson's disease (PD) likely requires delivery to both the degenerating cell bodies (in substantia nigra) and their terminals (in striatum). Prior to implementing this novel dosing paradigm in humans, we conducted eight nonclinical experiments with three general objectives: (1) evaluate the feasibility, safety and effectiveness of targeting the substantia nigra (SN) with AAV2-NRTN, (2) better understand and appraise recent warnings of serious weight loss that might occur with targeting the SN with neurotrophic factors, and (3) define an appropriate dose of AAV2-NRTN that should safely and effectively cover the SN in PD patients. Toward these ends, we first determined SN volume for rats, monkeys and humans, and employed these values to calculate comparable dose equivalents for each species by scaling each dose, based on relative SN volume. Using this information, we next injected AAV2-GFP to monkey SN to quantify AAV2-vector distribution and confirm reasonable SN coverage. We then selected and administered a ~200-fold range of AAV2-NRTN doses (and a single AAV2-GDNF dose) to rat SN, producing a wide range of protein expression. In contrast to recent warnings regarding nigra targeting, no dose produced any serious side effects or toxicity, though we replicated the modest reduction in weight gain reported by others with the highest AAV2-NRTN and the AAV2-GDNF dose. A dose-related increase in NRTN expression was seen, with the lower doses limiting NRTN to the peri-SN and the highest dose producing mistargeted NRTN well outside the SN. We then demonstrated that the reduction in weight gain following excessive-doses can be dissociated from NRTN in the targeted SN, and is linked to mistargeted NRTN in the diencephalon. We also showed that prior destruction of the dopaminergic SN neurons via 6-OHDA had no impact on the weight loss phenomenon, further dissociating neurotrophic exposure to the SN as the culprit for weight changes. Finally, low AAV2-NRTN doses provided significant neuroprotection against 6-OHDA toxicity, establishing a wide therapeutic index for nigral targeting. These data support targeting the SN with AAV2-NRTN in PD patients, demonstrating that properly targeted and scaled AAV2-NRTN provides safe and effective NRTN expression. They also provided the means to define an appropriate human-equivalent dose for proceeding into an ongoing clinical trial, using empirically-based scaling to account for marked differences in SN volume between species.

Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains.

BACKGROUND: AAV2-neurturin (CERE-120) is designed to deliver the neurotrophic-factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic-factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). METHODS: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2-neurturin in brains of PD patients versus those of nonhuman primates similarly treated. RESULTS: NRTN-immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral-NRTN was observed in all monkeys. NRTN-expression was associated with occasional, sparse TH-induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH-induction throughout the nigrostriatal neurons. DISCUSSION: These data provide the first evidence that gene therapy can increase expression of a neurotrophic-factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon-transport deficits reduced the bioactivity of AAV2-NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic-factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved.

An unusual injury to the first metatarsophalangeal joint.

Subtle but significant peripheral injuries can be overlooked in the multiply injured patient. We present one such case in relation to the first metatarsophalangeal joint, where failure to diagnose and treat early would have produced greater long-term morbidity.

Expression, bioactivity, and safety 1 year after adeno-associated viral vector type 2-mediated delivery of neurturin to the monkey nigrostriatal system support cere-120 for Parkinson's disease.

OBJECTIVE: Parkinson's disease is characterized by profound motor deficits that result mainly as a consequence of degeneration of midbrain dopaminergic neurons. No current therapy slows or halts disease progression. Neurturin (NTN) and glial cell line-derived neurotrophic factor have potent neuroprotective and neurorestorative effects on dopaminergic neurons, but their use in treating Parkinson's disease has been limited by significant delivery obstacles. In this study, we examined the long-term expression, bioactivity, and safety/tolerability of CERE-120, an adeno-associated virus type 2 vector encoding human NTN, after bilateral stereotactic delivery to the striatum of nonhuman primates. METHODS: Twelve naïve rhesus macaques received bilateral stereotactic injections of 1 of 2 CERE-120 doses or vehicle to the caudate and putamen. Neurological and clinical parameters were monitored for up to 1 year postadministration, after which animals were sacrificed for histological analyses. RESULTS: Dose-related NTN expression was observed at 1 year and was associated with enhanced tyrosine hydroxylase immunolabeling in the striatum, hypertrophy of tyrosine hydroxylase-positive cells in the substantia nigra, and induction of extracellular signal-regulated kinase signaling in the substantia nigra. Extensive, formal analyses, conducted in accordance with Good Laboratory Practice Regulations, across multiple time points revealed no evidence of clinical, neurological, or systemic toxicity. CONCLUSION: The present study provides evidence of long-term expression and bioactivity of NTN on the dopaminergic nigrostriatal system after bilateral stereotactic delivery of CERE-120 to the striatum. Furthermore, no evidence of any adverse effects for up to 1 year postadministration was observed. These findings reveal a wide safety margin for CERE-120 and collectively support the ongoing clinical testing of the efficacy and safety of CERE-120 in patients with Parkinson's disease.

AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease.

Neurturin (NTN) is a neurotrophic factor with known potential to protect and restore the function of dopaminergic substantia nigra neurons whose degeneration has been most closely linked to the major motor deficits in Parkinson's disease (PD). CERE-120, an adeno-associated virus serotype 2 (AAV2)-based gene delivery vector encoding human NTN, is being developed as a potential therapeutic for PD. In a series of preclinical studies reported herein, CERE-120 delivery to the striatum produced a dose-related neuroprotection of nigrostriatal neurons in the rat 6-hydroxydopamine (6-OHDA) lesion model. Long-lasting efficacy of CERE-120 was evidenced by substantia nigra cell protection, preserved fiber innervation of the striatum, and behavioral recovery for at least 6 months. In addition, striatal infusion of CERE-120 was found to have a safety and tolerability profile devoid of side effects or toxicological responses, for at least 12 months post-treatment, even at dose multiples 125 times that of the lowest efficacious dose tested. These results support the ongoing CERE-120 clinical program in PD patients.