RESEARCH DIVISIONS

Clinical Research

ALS Program and Neuromuscular

One of the primary goals of the ALS Program is to participate in clinical drug trials to find the cause and effective treatment and cure for ALS. The University of Miami ALS Clinical Trials Division is part of an international group of centers involved in trials to develop new drugs to treat ALS.

Nerve growth factors are proteins present in the normal nervous system that play a major role in the development of the embryonic nervous system and may play a role in nervous system regeneration. It is believed that they might be able to slow down the rate of degeneration or improve the rate of repair in such diseases as ALS. They have been shown to do so in animal models of ALS.

Our researchers have been involved in trials of ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF). CNTF and GDNF did not improve ALS patients, and were not well tolerated. The initial large trial of subcutaneous BDNF showed that it was well tolerated, but did not show an overall benefit. However, there was an apparent benefit in some groups of patients. Therefore, the BDNF trials are continuing.

In the study that we are participating in, patients are receiving high doses of BDNF subcutaneously. In another trial (at a variety of other centers) patients are receiving BDNF into the fluid that surrounds the brain and spinal cord (the cerebrospinal fluid) by means of a pump implanted under the skin like a pacemaker. Both of these trials are still ongoing.

Our researchers are part of an international collaborative study of a new drug, xaliproden, produced by the Sanofi-Synthelabo. Taken orally, this drug is absorbed from the gut and can enter the central nervous system, acting as a nerve growth factor stimulant. The two studies were double-blind placebo controlled investigations in which patients received either one or two milligram doses active drug or placebo each day. The trial lasted 18 months, and the patients continue to receive open label active drug treatment.

In one study, all patients were co-treated with riluzole. In the other study patient were treated with xaliproden alone. The trials are now completed and analyzed. The drug was well tolerated. There was a general trend for the drug to produce a slowing down of the progression of ALS by 10 to 20 percent. However, statistical confirmation of this benefit was seen in only of the studies, and the effect was less in patients co-treated with riluzole. The implications of these results are still under discussion.

It is likely that there will be new trials of other neurotrophin stimulant drugs that can be taken by mouth. In the meantime we are involved with a number of other multicenter trials of already available drugs to determine if they will produce a benefit in ALS.

Search for New Genes Causing ALS
We also are collaborating with the laboratory of Robert Brown, M.D. in Boston; in projects to discover more of the genes responsible for familial ALS, and also to discover the genes that either make sporadic ALS patients susceptible to or protected against developing ALS.

Researchers now believe that the disease process in ALS functions as a cascade. There are predisposing factors, particularly gene mutations like those in SOD1 that predispose a person to develop ALS. Brown is looking for these susceptibility genes, working with us and with other collaborators.

Investigation of the Preclinical Stages of ALS
We do not know what happenes to the motor neurons in the years and decades before patients with ALS develop symptoms. An answer to this question would provide us with insight into the biochemical processes leading to motor neuron degeneration. Researchers are studying the motor neuron function in children of patients with familial ALS to determine the answer to this question. Anyone with a family history of ALS who is interested in taking part in this study should contact us via e-mail at wbradley@med.miami.edu.

Research Into the Clinical Care of ALS Patients
We participate in the ALS Care Program that provides a national registry and data bank on ALS patients. As a result, we are able to undertake research to compare the outcomes of treatment of our patients in the Kessenich Family MDA ALS Center with national figures. A home visit program is also available for homebound and ventilator-dependent patients that are being evaluated for the purposes of this research.

In addition, we participated in the American Academy of Neurology Program to develop the Practice Parameter that describes the best ways to care for patients with ALS. This is the basis of a national and international education program to raise the standard of care of ALS patients and their families throughout the world.

Stroke/Neurovascular

Researchers within the department’s neurovascular laboratory perform ultrasound studies in cerebral hemodynamics using ultrasound techniques. This laboratory technique examines the vessels in the neck that transport blood to the brain and the vessels inside the brain using Transcranial Doppler.

These techniques allow doctors within the stroke division to look for the presence of blockages inside the brain, to catch a potential stroke before it strikes, and to take action even in those patients who are symptom free.

Clinical trials in several categories are conducted on a regular basis. For example, clinical trials that test drugs or strategies that improve the outcome of an acute stroke are regularly tested on patients with stroke symptoms.

In addition to the activities being conducted at the two stroke prevention clinics, the Jewish Home for the Aged, and other community locations, Alejandro Forteza, M.D., assistant professor in the Department of Neurology, has been focusing on stroke prevention and educational strategies. Forteza is presently heading a project that teaches school children and their parents about stroke. The program is an inexpensive way to bring health knowledge home.

Forteza also has been examining a condition called fat embolism syndrome, which generally develops after trauma involving long bone fractures. In such fractures, bone marrow enters the blood stream, later reaching the lungs. These fatty molecules return to the heart and eventually reach the brain, which may lead to permanent brain damage. This is particularly common after fractures of long bones, such as the bones of the extremities. Forteza has seen that this serious complication of fractures may be worsened by trying to correct the fracture, allowing more marrow to be “squeezed” out into the blood stream. This also may be the reason why so many hip and knee replacement surgeries have abnormal postoperative periods.

As a result of these findings, Forteza’s team is conducting research to detect the presence of fatty globules traveling to the brain through the use of Transcranial Doppler techniques. This research has garnered a national prize from the Dana Foundation.

Drs. Forteza and Koch have studied the development of brain symptoms following fractures and major surgery, including open heart surgery. They have found a clear association between the post-surgery or post-injury deterioration of mental function in such patients with a congenital abnormality of the heart called a patent foramen ovale (PFO). Patients with this condition are much more likely to have fatty globules and clots reach the brain with a fracture or open heart surgery. To avoid such complications, a simple surgical procedure can be performed to close the PFO between the right and left side of the heart before undergoing surgery or as soon as the patient experiences the fracture. Simple procedures such as an echocardiogram or Transcranial Doppler study can indicate if the patient has this condition.

Forteza’s laboratory also is studying the effect of statins, drugs that reduce cholesterol. Through the use of ultrasound, researchers are testing individuals at risk for having a stroke or those with abnormal cerebral hemodynamics. Patients were given statins and preliminary data found that these statins actually improved cerebral hemodymanics, meaning these individuals may be receiving other benefits that have nothing to do with cholesterol.

Epilepsy

No research information obtained from Epilepsy Division

Movement Disorders

Researchers within the Movement Disorder Division are conducting various studies relating to movement disorders.

• Dopamine agonists, or drugs that imitate the action of dopamine, the crucial substance that is decreased in the brain of patients with Parkinson’s disease. These studies include one dopamine agonist that is administered through the use of a patch and another one that is administered through an injection.
  
• Drugs that have an antiparkinsonian effect by virtue of novel mechanisms, adenosine antagonists.
  
• Comparison of two types of Botulinum toxin in the treatment of cervical dystonia, spasmodic torticollis.
  
• Genetic evaluation of patients with siblings, children or parents also affected with Parkinson’s disease.
  
• Observational studies of individuals at-risk to develop Huntington’s disease.

Sleep Disorders

The Sleep Disorders Center has an ongoing research program and has conducted ongoing research in a variety of sleep related trauma issues for over ten years.

Current research focuses on examining sleep disturbances in individuals after life threatening injuries, as well as a number of other sleep related trauma issues.

The NIH-funded research is a four-year project in association with the Ryder Trauma Center. This work is in collaboration with Thomas Mellman, M.D. at Dartmouth University. (Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B. REM sleep and the early development of post traumatic stress disorder. Am J Psychiatry 2002; 159:1696-1701.)

Neurorehabiliation

Current researchers in the Neurorehabilitation Division include Bruce Rubin, M.D., assistant professor of neurology, who has been involved in a collaborative investigation with the Department of Radiology studying MRI Spectroscopy changes of the brain in traumatic brain injury and how it relates to neuropsychological outcomes.

Other studies within the division include one conducted by Kester Nedd, D.O., associate professor, who is the principal investigator on the study titled Pulsed radio frequency lesioning of the suprascapular nerve in long-term pain control in patients with Shoulder pain.

NeuroAIDS

Ashok Verma, M.D., D.M., associate professor of neurology, has been studying HIV-1-associated neuropathies. He has found that approximately 30 percent of AIDS patients have clinical neuropathies. The incidence is likely to move up, as patients with HIV-1 infection survive longer on suppressive antiretroviral regimen. Additionally, several antiretroviral drugs have inherent neurotoxicity.

Understanding the mechanism of HIV-1 neuropathy and discovering strategies to arrest, reverse, and prevent neuropathic deficits is urgently required to effectively deal with the morbidity and disability associated with HIV-1 neuropathies.

Research earlier delineated one uncommon form (vasculitic) of HIV-1 neuropathy and its effective treatment. We have described HIV-associated neuropathies with lactic acidosis in patients receiving certain anti-retroviral drugs. Verma’s team investigated peripheral nerve involvement in a simian HIV model and are investigating anti-retroviral toxic neuropathy in a rodent model.

As a part of Neurologic AIDS Research Consortium (NARC) researchers are involved in investigating the efficacy and safety of prosaptide (saposins) in HIV-associated painful neuropathies.