Thalidomide and neurotrophism.

BACKGROUND: Following the thalidomide disaster (1958-62), Henkel and Willert analysed the pattern of dysmelia in the long bones (J Bone Joint Surg Br. 51:399-414, 1969) and the extremities, Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970). Willert's material from deformed extremities is re-examined here asking "How does thalidomide reduce the skeleton?" MATERIALS AND METHODS: We reviewed the original data collection of Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970), comprising musculoskeletal histology slides from 30 children affected by thalidomide with radiographs of hands (19 cases) and feet (4 cases). RESULTS: All original observations by Willert and Henkel (Z Orthop Ihre Grenzgeb. 107:663-75, 1970), were verified. Radial rays of the hand disappeared early, but the foot was spared until late. Radiology confirms that bone reduction in the hand (aplasia or hypoplasia in the thumb and index finger) coincides with sensory segmental nerve C6. In the foot, reduction of the toes is rare, but mesenchymal excess (polydactyly) occurs in the hallux (L5 sclerotome), usually associated with absent tibia (L4 sclerotome). Histology confirms skeletal mesenchymal components to be unremarkable, contrasting with grossly abnormal bony architecture, a striking discordance between microscopic and macroscopic findings. No necrosis or vascular pathology was seen. CONCLUSION: The basic lesion was an abnormal quantity rather than quality of mesenchyme. Cell populations result from cellular proliferation, controlled in early limb bud formation by neurotrophism. Thalidomide is a known sensory neurotoxin in adults. In the embryo, sensorineural injury alters neurotrophism, causing increased or diminished cell proliferation in undifferentiated mesenchyme. Differentiation into normal cartilage occurs later, but within an altered mesenchymal mass. Reduction or excess deformity results, with normal histology, a significant finding. The primary pathological condition is not in the skeleton, but in the nerves.

Deep brain stimulation for Parkinson's disease: Australian referral guidelines.

The advent of deep brain stimulation (DBS) has been an important advance in the treatment of Parkinson's disease (PD). DBS may be employed in the management of medication-refractory tremor or treatment-related motor complications, and may benefit between 4.5% and 20% of patients at some stage of their disease course. In Australia, patients with PD are reviewed by specialised DBS teams who assess the likely benefits and risks associated with DBS for each individual. The aim of these guidelines is to assist neurologists and general physicians identify patients who may benefit from referral to a DBS team. Common indications for referral are motor fluctuations and/or dyskinesias that are not adequately controlled with optimised medical therapy, medication-refractory tremor, and intolerance to medical therapy. Early referral for consideration of DBS is recommended as soon as optimised medical therapy fails to offer satisfactory motor control.

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease.

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinson's disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Long-term follow-up of DBS of thalamus for tremor and STN for Parkinson's disease.

In 1994 we commenced deep brain stimulation (DBS) of the thalamus for patients with severe tremor. This was done under the guidance of Professor Alim Benabid from Grenoble, France, who pioneered the technique. In the beginning we commenced DBS of the thalamus for patients with severe tremulous Parkinson's disease, essential tremor, and in one case, severe post-traumatic tremor. In all, we had 28 patients for whom the procedure was performed for tremulous Parkinson's disease, six patients with essential tremor and one patient with post-traumatic tremor. In 1997, again under the guidance of Professor Benabid, we commenced bilateral subthalamic nucleus stimulation (STN) for patients with severe Parkinson's disease. We were the second unit in Australia to become established for these procedures. A total of 45 patients have undergone STN DBS and have been followed up on a regular basis by the same neurologist (DOS). The surgical complications and long-term complications, including hardware problems will be reviewed retrospectively, as well as the long-term benefits of these surgical procedures.

Pallidal stimulation reduces treatment-induced dyskinesias in "minimal-change" multiple system atrophy.

Deep brain stimulation therapy is increasingly gaining acceptance in the management of levodopa-induced dyskinesia and fluctuations in idiopathic Parkinson's disease. It is generally not recommended for the other forms of parkinsonism such as progressive supranuclear palsy or multiple system atrophy where the response to levodopa is usually poor and disease progression more rapid, making any benefit short-lived. Here, we present an autopsy-confirmed case of "minimal-change" multiple system atrophy in whom pallidal stimulation surgery was effective in abolishing severe levodopa-induced dyskinesia.

Partial lesion of thalamic ventral intermediate nucleus after chronic high-frequency stimulation.

A 73-year-old man with Parkinson's disease underwent thalamic stimulation for disabling tremor with excellent results only when stimulation on. Post-mortem neuropathology (7 years postoperatively) revealed 60% cell loss within 0.5 mm of the electrode tip. Tremor improvement was attributable to chronic stimulation, not microthalamotomy.

Postmortem analysis of bilateral subthalamic electrode implants in Parkinson's disease.

This is the second neuropathological report detailing bilateral electrodes targeting the subthalamic nucleus (STN) in idiopathic Parkinson's disease (PD). The patient presented with unilateral tremor-dominant parkinsonism. Bilateral STN stimulation was carried out 7 years later due to significant disease progression and severe motor fluctuations. The patient exhibited bilateral improvements in rigidity and bradykinesia both intraoperatively and postoperatively. The patient died 2 months later from aspiration pneumonia. Neuropathological examination confirmed both the diagnosis of PD and the electrode placements. The tip of the left electrode was located medially and posteriorly in the left STN and the tip of the right electrode entered the base of the thalamus/zona incerta immediately above the right STN. Tissue changes associated with the subthalamic electrode tracts included mild cell loss, astrogliosis, and some tissue vacuolation. Our postmortem analysis indicates little tissue damage associated with STN stimulation for PD.