THE FOUNDATION & ALS

Making a correct diagnosis – Is it ALS or not?

Doctor Pioro sees on average, three new patients per week who carry a possible diagnosis of Lou Gehrig’s disease, most of them referred to him for a second opinion from surrounding areas in Ohio, out of state, or elsewhere. After the appropriate investigations are performed, over three-quarters of such patients will unfortunately receive the diagnosis of ALS or motor neuron disease (MND), a related diagnosis which lacks the specific features of Lou Gehrig’s disease. However, some will be found to have less serious conditions which were mistaken for ALS, ranging from curable conditions to chronic neurologic disorders which are incurable but usually not fatal. For example, certain myopathies or dystrophies (types of muscles disorders) can be mistaken for a lower motor neuron form of MND, whereas multiple sclerosis or spinal cord compression can be mistaken for an upper motor neuron form of MND.

A definition of ALS and other motor neuron diseases

ALS is the most frequent of the MNDs, which as a group are progressive and incurable degenerative diseases affecting motor neurons of the brain and spinal cord. Motor neurons in the brain are concentrated in the motor cortex and can be thought of as the ‘power station’ or ‘1st relay station’, which produces the initial signal whenever speech, swallowing or movement is initiated. These motor neurons are known as the ‘upper’ motor neurons (UMNs). From here, messages are sent along axons (nerve tracts) to groups of motor neurons located in the brainstem (lower part of the brain), or in the spinal cord. These ‘2nd relay station’ neurons, known as the ‘lower’ motor neurons (LMNs), in turn send their axons to the muscles of the body, stimulating them to contract and cause movement. This is illustrated by the cartoon of the brain, spinal cord and muscles in Figure 1, where the UMNs and their pathways to the LMNs are shown in red and the LMNs and their pathways to the muscles are shown in green. MNDs can affect either group of motor neurons separately or together. If separately, this results in conditions like primary lateral sclerosis (PLS) when only the UMNs are affected, or progressive muscular atrophy (PMA) when only the LMNs are affected. ALS occurs if there is combined dysfunction of both UMNs and LMNs in the absence of other conditions to explain it.

Clinical care of patients with ALS and other MNDs is a team effort

Seven other neuromuscular subspecialists and several other neurologists in the Department of Neurology also evaluate patients coming to the CCF with a possible diagnosis of Lou Gehrig’s disease. “Last year alone, about 300 patients were given the first time diagnosis of ALS or MND in the department”, reports Dr. Pioro, “and over 200 patients each year are provided ongoing care in the Center for ALS and Related Disorders by professionals in our ALS Association-certified multidisciplinary ALS/MND Team Clinic.”

As director of the CCF Center for ALS and Related Disorders, Dr. Erik Pioro devotes about half of his time to the care of patients with ALS and other MNDs by providing clinical consultation, ongoing management, and running of clinical trials to identify novel drugs for the treatment of ALS. This requires the assistance of two dedicated individuals: his ALS clinical nurse coordinator, Kathleen Kelly, MSN, CNS, a nurse practitioner with extensive experience in palliative care, and his clinical research coordinator, Kim Law, CCRP, CCRC, who attends to the daily workings and running of ALS clinical trials.

Ongoing care for patients with ALS and other MNDs is provided on a regular basis by Dr. Pioro and the ALS/MND multidisciplinary team. During the half-day Team Clinic, several patients are individually assessed and treated by Dr. Pioro or his assistant (Dr. Rebecca Kuenzler) and members of the team: physical therapists (Matt Sutliff, Michelle Harrison), occupational therapist (Gloria Morin), nutritionist/dietician (Arlene Escuro), speech pathologist (Mary Trombold), social worker (Angela Clay), and nurse. During the focused session with each health care professional, patients and their caregivers are educated in maximizing function and quality of life. A representative from the local ALSA chapter is also available to assist with patient needs. Additional half day clinics provide more focused ongoing care by Dr. Pioro and his nurse practitioner for patients in between their regularly scheduled larger Team clinic visits. Close collaboration is maintained for specialized care and treatment, when necessary, by individuals in the Departments of Pulmonology and Critical Care (Dr. Loutfi Aboussouan), General Surgery (Dr. Matthew Walsh), Gastroenterology, Dentistry (Dr. Salvatore Esposito), Psychology, and Palliative Medicine.

Active drug treatment trials for ALS are ongoing at CCF

The Cleveland Clinic’s Center for ALS and Related Disorders is at the forefront in finding a cure for ALS and related motor neuron diseases. As principal investigator, Dr. Pioro and the Center have recently participated in several multicenter clinical trials, evaluating Xaliproden, topiramate (Topamax®), creatine monohydrate, Neurodex® (AVP-923), celecoxib (Celebrex®), and TCH346. With the exception of Neurodex, unfortunately none of these drugs showed statistically significant benefit in patients with ALS, despite positive results in preclinical animal studies. One ongoing trial (although closed to enrollment) is re-examining whether insulin-like growth factor, type I (Myotrophin®) will successfully retard the progression of ALS. The answer should be known within the next two years. Three new ALS multicenter clinical trials testing both oral and intravenously administered medications will begin recruitment of patients soon in the Center for ALS and Related Disorders.

Basic laboratory research is vital to finding a cure for ALS and other MNDs

The other half of Dr. Pioro’s time is spent performing research in his lab in the Department of Neurosciences at the Lerner Research Institute on molecular mechanisms of motor neuron degeneration in experimental mouse models of ALS. A team of two post-doctoral fellows (Dr. Volodymyr Kostenko and Dr. Jialin Zhang) and a lab technician (Qi Yu) is instrumental in experiments performed in the lab. Other research by Dr. Pioro involves MRI and other techniques to identify motor pathway degeneration in the brains of patients with ALS. This is done in collaboration with Dr. Michael Phillips in the Department of Neuroradiology, and Dr. Guang Yue in the Department of Biomedical Engineering.

Dr. Pioro’s laboratory in The Cleveland Clinic Lerner Research Institute focuses on identifying molecular pathways leading to motor neuron degeneration by studying two mouse models of ALS. These include the wobbler mouse, a spontaneous mutant closely resembling human ALS in which the responsible gene is not yet known, and a transgenic mouse overexpressing a mutated copper-zinc superoxide dismutase (SOD1) gene, as found in some patients with hereditary ALS.

As in ALS, protein breakdown appears to be abnormal in wobbler mouse spinal cord and brain, resulting in accumulation of potentially damaging intraneuronal aggregates. Figure 2 shows two wobbler motor neurons in the cortex (arrows) with abnormal aggregates which contain ubiquitin-tagged protein. Identifying the proteins which accumulate and the mechanisms by which this happens may lead to novel treatments to prevent motor neuron degeneration and even identification of the wobbler gene.

The immune system has recently been implicated in the progression of ALS. Using SOD1 transgenic mice (mice genetically engineered to have an abnormal mutation of the human SOD1 gene), Dr. Pioro and Dr. Richard Ransohoff (Dept. of Neurosciences) are seeking to determine whether microglia, a key component of the CNS immune system, contribute to motor neuron degeneration. Microglia are kept under control by a certain receptor which if genetically removed, appears to allow them to be activated. Although this activation can sometimes be helpful, as in fighting an infection, it can also be harmful. By replacing the receptor with a green fluorescent label in the SOD1 transgenic mice, the microglia can be clearly seen under a microscope.

Figure 3 shows normal small microglia (colored green) in the spinal cord of healthy mice (A), more numerous and larger microglia in the transgenic mouse with ALS (B) and very numerous and more activated appearing microglia in the ALS mouse in which the receptor has been completely removed. Drs. Pioro and Ransohoff have found that activation of microglia in SOD1 ALS mice results in increased motor neuron death and more rapid disease progression. Microglia in human ALS may also be causing motor neuron degeneration because this same receptor may not work normally in some individuals allowing their activation. Experiments are planned to characterize gene pathways involved in this microglia-mediated neuronal death so that novel treatments can be found to block it and slow ALS progression.

Especially promising areas of interest involving the wobbler mouse include retarding disease progression by incorporating a gene mutation (slow wallerian degeneration, WLDs) known to delay axonal degeneration and identifying the gene pathways responsible for such disease slowing. Wobbler mice expressing the WLDs gene (WLDs positive) retain a significant amount of muscle strength and bulk, and have less brain and spinal cord loss compared to wobbler mice without the WLDs gene (WLDs negative). As shown in Figure 4, wobbler mice negative for the WLDs gene have more degenerating spinal cord motor neurons (arrows in top left) and have a dramatic decline in grip strength (bottom) whereas those positive for the WLDs gene have fewer degenerating neurons (arrow in top right) and retain grip strength, even with some later recovery (bottom). Future studies will test whether muscle weakness in wobbler mice can be delayed or reduced after administration of the WLDs gene directly into the nerves or muscles of mice once disease has begun. Validating the effectiveness of this gene therapy in wobbler mice with ALS is necessary before proceeding to human clinical trials.

 

Finding a cure for ALS is a task we will accomplish together

“Working with ALS patients is a challenge but it is also an honor. It is extremely satisfying because they are some of the bravest and most amicable people I have ever met,” states Dr. Pioro. “This is in part what allows me to keep doing what I do, along with knowing that I am contributing, at least in some small way, to finding a cure for this disease and put an end to it once and for all. Until we do find a cure, however, the clinical experts in the Department of Neurology and the Center for ALS and Related Disorders are here to help our patients live each day to the fullest.”