Electrophysiology of Neurons (The Neuron) Part 4

Guillain-Barre Syndrome  

Multiple Sclerosis

The cause of multiple sclerosis (MS) is unknown. It may be an autoimmune disease with inflammatory features that affect the CNS. It should be recalled that oligodendrocytes (not Schwann cells) provide myelination in the CNS. The body erroneously directs antibodies against proteins in the myelin sheath in the CNS. Thus, demyelination occurs in the axons of the CNS, whereas demyelination of axons in the peripheral nerves occurs in Guillain-Barre syndrome.Antibodies attack myelin, which then swells and detaches. A scar (sclerosis) develops on the nerve fibers, which delays or blocks nerve impulses. Finally nerve fibers degenerate. MS is a debilitating disease that commonly affects young people, especially women, in the 20-year-old to 40-year-old age group. Somatosensory pathways are compromised in MS, resulting in numbness in one or more limbs, typically on one side. The patient feels tingling or pain in parts of the body. Visual pathways are affected, resulting in vision disturbances (partial or complete loss of vision in one eye at a time and double or blurred vision). The patients suffer from disturbances in speech. Electric shock-like sensation is experienced by the patient when the head is moved. In MS, typically the white matter of the cerebellum, spinal cord, and projections of the corticospinal tract and basal ganglia are affected, causing upper motor neuron weakness. There is weakness in one or more limbs on one side. The patient has tremor, lack of coordination, wide steps, and an unsteady gait. Other symptoms include fatigue and dizziness. Neurological examination shows hyper-reflexia and Babinski’s sign. Magnetic resonance imaging shows scarring in the CNS. Assessment of the slowing of conduction in the optic nerves of these patients is used as one of the tests of this disease. Conduction in the optic nerve is tested by applying a visual stimulus, consisting of a checkerboard pattern, and monitoring the visual evoked potentials from the scalp. Management of these patients includes administration of the drugs or procedures shown in Table 6-3. A clinical case of multiple sclerosis is presented at the end of this topic.

Prion Diseases

A prion is an infectious agent consisting primarily of protein. The endogenous form of prion protein (PrP) is referred to as PrPc. A misfolded form of PrP is designated as PrPSc. The normal form of PrP is present in cell membranes of many tissues. It is believed that the infectious form of prion protein (PrPSc) converts normal prion protein (PrPc) into infectious form by changing its  conformation.

TABLE 6-3 Drugs or Procedures Used to Treat Multiple Sclerosis

An amyloid fold is produced in which the protein polymerises forming aggregates of tightly packed beta sheets (see "Structure of Proteins" in the beginning of the topic). The protein aggregates (amyloids) formed in this manner are resistant to chemicals, proteases, heat and radiation. Effective prion decontamination can be achieved by treatment with bleach, caustic soda, and strong acidic detergents. The misfolded form of prion protein (i.e., PrPSc) has been implicated in several diseases including Creutzfeldt-Jakob Disease, Kuru and bovine spongiform encephalopathy (mad cow disease). Creutzfeldt-Jakob disease, also called subacute spongiform encephalopathy, is characterized by widespread neuronal loss and gliosis accompanied with vacuolation in the affected brain regions (predominantly cerebral and cerebellar cortices) giving them a spongy appearance. A rapidly progressive and profound dementia occurs which is accompanied by myoclonic jerks and visual and cerebellar neurological abnormalities. There is no effective treatment for this disease. The patients usually die within a year of the onset of the disease. Kuru is a disease that afflicts exclusively the natives of New Guinea. It is believed that these natives ingest the brain tissue of deceased relatives which may contain infectious form of prions. The disease is characterized by progressive cere-bellar ataxia and weakness that eventually leads to immobility. The patients usually die within 3-6 months of the onset of the disease. The disease has largely disappeared because this type of ritual cannibalism is no longer practiced by these natives. The infectious agent in bovine spongiform encephalopathy (mad cow disease) is also a misfolded prion. The disease is characterized by spongy degeneration of the brain and spinal cord in cattle. Although cattle are normally herbivores, they may be infected when they are fed meat and bone meal prepared from the carcasses of infected cattle. It is believed that the disease may be transmitted to humans who eat the brain and spinal cord of infected carcasses.

Cystic Fibrosis

Cystic fibrosis is an inherited disease that affects primarily the respiratory system (airways and the lungs). It is a recessive disorder (i.e., a person is afflicted with this disease when he or she inherits a copy of the mutated gene from each parent). In humans, cystic fibrosis transmembrane conductance regulator gene (CFTR gene) is located on chromosome 7. This gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator protein (CFTR protein). This protein is located in the cell membrane and functions as an ion channel through which Cl- ions are transported into the cells and movement of water into the tissues is controlled to maintain the fluidity of mucus and secretions. Tissues that produce mucus, sweat, saliva, tears, and digestive enzymes have such channels. These channels are necessary for normal secretions in organs such as the lungs and pancreas. In cystic fibrosis there is a mutation of CFTR gene. The genetic mutation stops production of CFTR protein in the cells of the lungs (and other organs, e.g., pancreas). The lack of this protein impairs the function of Cl- channels. Thus, the ability of these cells to transport Cl- in and out of cells is impaired, which changes the chemical properties of secretions, causing the mucus to be thicker than normal. This, in turn, leads to obstructions in the respiratory tract and creates conditions ideal for repeated infections. Management of the respiratory symptoms of the disease includes administration of antibiotics (for treating infections), decongestants and bronchodilators (to open airways), steroids (to reduce inflammation), chest or back clapping (to help loosen mucus from lungs), and postural drainage (to help drain mucus from lungs).

Clinical Case

History

Martha is a 33-year-old woman who, until several months ago, was a normal, healthy individual who exercised regularly. She maintained an administrative position in the Department of Neurology at a northeastern medical school. On three separate occasions over the past 2 months, she began to experience weakness and numbness in her right arm and leg. In addition,she began to have double vision and experienced a sensation as if insects were moving along the right side of her face and tongue. She consulted her physician, who then referred her to a neurologist.

Examination

The neurological examination revealed some nystagmus when Martha attempted to look to the right, some depressed vision in her right eye, weakness of the right eye when medial gaze was attempted, and some weakness of the right facial muscles. She also showed some tremor when attempting to point to her nose, a wide ataxic gait, and general difficulty in walking. The evoked potentials test revealed a longer-than-normal latency for the visual evoked response following stimulation of the right eye. A magnetic resonance imaging (MRI) scan of the head indicated the presence of what appeared to be small lesions over widespread regions of the brain. A lumbar puncture was done to collect a cerebrospinal fluid sample that, on subsequent analysis,showed an increase in gamma globulin level above normal values.

Explanation

Martha was diagnosed with multiple sclerosis (MS),a syndrome described earlier in the text of this topic. The MRI showed that there was no single locus of a lesion. Instead, a variety of lesions seemed to be present, affecting both sensory and motor systems, and visual evoked potential testing revealed slower conduction velocity along visual neuronal pathways. These symptoms are consistent with a diagnosis of MS. MS is a debilitating disease that commonly affects young people, especially women in their 20s to 40s. It typically affects such systems as the white matter of the cerebellum; spinal cord;and projections of the corticospinal tract and basal ganglia, causing an upper motor neuron weakness as well as sensory systems, such as the visual and somatosensory pathways, resulting in numbness and some loss of vision.

The course of this disease can vary. There may be no recurrence after the first event. In other cases, there may be a series of episodes followed by periods of remission. In the worst cases, the disease is progressive in which few or no periods of remission are present. Treatment strategies include the administration of steroids. Another treatment includes administration of interferon P-1 b, which has been shown to reduce the frequency and severity of relapses. In the case of Martha, she was treated with oral prednisone in the hospital for 5 days. She showed an excellent recovery and soon resumed her professional life.

SUMMARY TABLE

Ion Channels

Na⁺ = sodium; K⁺ = potassium; CFTR = cystic fibrosis transmembrane conductance regulator; Cl" = chloride; Ca²⁺ = calcium; Ach = acetylcholine;NMJ = neuromuscular junction.

"Cystic fibrosis is not a neurological disease.lt is discussed in the context of defects in ion channels.