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Itai-itai disease was found in the cadmium polluted Jinzu river drainage in 1913 down stream from the Mitsui Mining and Smelting Company. The disease gets its name from the cries of pain elicited by its victims, Itai-itai or “ouch ouch”. In 1955, Dr. Hagino suspected cadmium as the cause of the disease. The disease was officially recognized in 1968 by the Ministry of Health as the first disease caused by environmental pollution. (Slide 2) The epidemiology of cadmium poisoning could only explain the occurrence of the disease in specific areas around the Jinzu River. The degree of cadmium pollution determined by soil analysis strikingly compared with the disease occurrence. (Slide 3) There were other areas of Japan that were also affected but the highest concentration occurred along the Jinzu River in the Toyama Prefecture. 95% of the victims were post-menopausal women who had born multiple children. (Slide 4) The disease started with symptoms similar to rheumatism, neuralgia, or neuritis. Renal tubular dysfunction accompanied by pathologic bone fractures and lesions followed.
In the mid 1960s, Dr. Gabbiani and Dr. Baic reported that a single subcutaneous injection of cadmium chloride produced hemorrhagic lesions and nerve cell necrosis in sensory ganglia in rats. Other investigators have also demonstrated the toxic effects of cadmium in other regions of the brain, autonomic ganglia, peripheral nerves, and the neuromuscular junction. Much of the current information is based entirely on animal studies. The toxic effects of cadmium on the human nervous system requires more study, however it seems there is a dramatic effect in mammals such as rats, mice, and guinea pigs a very short time after exposure to a minuscule dose. Considering the wide spread nature of this pollutant, it seems fairly clear that neurological side effects in humans occurs. For example, in 1997 Okuda studied a man who had suffered from acute cadmium poisoning. Three months after exposure, he developed Parkinsonian like symptoms.
Another prominent finding is the accumulation of glycogen particles in glycogenosomes of the axoplasm. Hamada, in 1981, showed there is a buildup of glycogenosomes in the sciatic nerves in neuropathy induced by cadmium exposure in rats. Mercury exposure also induced neuropathy, but there were no glycogenosomes. Cadmium has been shown to inhibit the activity of alpha-glycosidase in tissue cultures. The glycogen particles are then engulfed by the lysosomes.
Cadmium may inhibit neuromuscular transmission by inhibiting calcium function at the presynaptic junctions. Cooper has suggested that cadmium is more effective than lead at blocking the passage of calcium through the pre-synaptic membrane. Arvidson, in 1979, described that a single dose of cadmium produced severe endothelial cell damage.
It is always a mystery to me how things in my life become intertwined. While beginning my education in neuromuscular dentistry I was constantly reminded of the study I embarked on as a student at Michigan. I was lucky to work with Dr. Dusan Baic in 1980 at the University of Michigan. When I listen to Dr. Thomas lecture about the nervous system in great detail, the hundreds of electron micrographs I had prepared, and stored for years in my basement, began to speak to me. (Slide 5)
Electron microscopy of the nervous system is tricky. If one is looking for pathology, care must be taken. The moment the animal dies hypoxia occurs and nerve cells degenerate. You may be looking at an artifact of the fixation. In this study I used a technique of vascular profusion on laboratory mice to prepare the specimens. I don’t want to bore you with the gory details. A detailed description of how to manage the specimens for electron microscopy could take about an hour or more.
(Slide 6)The first slide shows a group of cells in the Gasserian ganglion. Nerve cell bodies (bottom and upper left) with abundant mitochondria and aggregations of ribonucleic protein granules called Nissle substance. The nucleus of a nerve cell occupies the lower right and is limited by a porous membrane. Encapsulating the nerve cell bodies are satellite cells. The cytoplasm of the nerve cell is lighter than that of the satellite cell. Note the close approximation of cells with limited intracellular space.
Inter-digitations between the satellite cell and the nerve cell exist. Two myelinated nerve fibers are present in close contact with their Schwann cells and satellite cells (center). Their myelin sheaths vary in thickness. Collagen is dispersed in the endoneurium between the Schwann cells.
(Slide 7) The next micrograph show an interesting phenomena; in the lower half of the picture is a Schwann cell beginning to myelinate the nerve axon of this young mouse. Protrusions of myelin into the surrounding cytoplasm can be seen. In the lower portion of the cell are the wide cisternae of the granular endoplasmic reticulum. (Slide 8) Ribosomes are attached to the endoplasmic reticulum. Clusters of free ribosomes in rosettes form Nissle bodies throughout the cytoplasm and along the nuclear membrane. The nucleus of the Schwann cell is darkly staining and contains clumps of chromatin. Within the light cytoplasm of the nerve fibers, mitochondria, microtubules, and neurofiliaments can be seen.
(Slide 9) This micrograph of the Gasserian ganglion shows various sizes of nerve cell fibers. Schmidt-Lantermann clefts can be seen. These represent areas where the lamellae of the sheath has buckled into the cytoplasm as the Schwann cell is myelinated the axon. Collagen fibrils can be seen in the endoneurium.
(Slide 10 & 11) Here are micrographs with a variety of different sized axons. The cells are densely packed. The axons are all in close proximity and surrounded by their satellite cells.
(Slide 12) Let’s take a look at what happens five hours after administration of an injection of 1mg cadmium chloride. The intracellular space between the cells is enlarged as a result of edema. This is consistent with rapid endothelial breakdown. We do not see hemorrhagic infiltrates at this stage. This seems to occur after 24 hours. The nerve fibers do not show pathologic changes, except there is fluid build-up in the myelin layers. The satellite cell shows nuclear pyknosis. This clumping of chromatin to the periphery of the nucleus or movement of the nucleolus is a precursor to cellular death. Look at the dark staining lysosomes in the axons. Years ago when I first looked at these I thought the axons showed no pathology however it seems these lysosomes are more distinct here indicating the metabolic failure of alpha-glycosidase.
(Slide 13) The next micrograph is even more dramatic. This is a large cell body undergoing cellular death. Look at the nuclear pyknosis and widening of the porous nuclear membrane. The Golgi apparatus, mitochondria and Nissle bodies (these are clumps of ribosomes arranged in rosettes). The satellite cell is separated along the boundaries of the nerve cell. Look at the darkly staining lysosomes. The substance that stains that dark is glycogen. The glucose metabolism of this cell has been inhibited. There is massive edema in the cellular spaces. Note the lack of collagen. Do you think this animal is suffering some form of neuritis?
When I first looked at these slides I totally overlooked the lysosome connection! I thought there’s the typical intracellular edema. I did notice the dark lysosomes, but I never made the connection to glycogen inclusion bodies and the metabolic interruption occurring within the cell. I dug this out of my basement, and then discovered what has really happened.
(Slide 14) Let’s take a closer look on comparison. Do you think the cells on the right have lost their intracellular communication? See the ribosomes scattered throughout the cytoplasm?
It was only a few months ago when I realized we had a perfect example of this lysozome phenomena, not in the axons themselves, but in the nerve cell bodies five hours after exposure. (Slide 15) The interesting thing is, you could probably treat these thin sections with alpha-amylase or alpha-glucosidase and actually digest the glycogen right out of the lysosomes. You could then compare one thin section to another. I would expect to see the lysosome bodies completely devoid of material. As it turns out we were studying the morphology of liver glycogen at the exact same time! In a study with Dr. Baic I showed this to work quite well with muscle glycogen. (Slide 16) If I had realized the connection we would have clearly performed this test on the lysosomes of the nerve cell bodies.
This study demonstrates that a small amount of cadmium has a direct toxic effect on nerve cells. The moral of this is really about being extremely careful about cadmium exposure. It is in so many products and very common as an environmental pollutant. A very small amount of cadmium may have an immediate impact in sensory ganglia particularly the trigeminal nerve. What role would TENS have in rehabilitating these patients? When we evaluate patients with neuralgias and neuromuscular dysfunction we may want to consider heavy metal poisoning. What’s in your basement? (Slide 17)
Dr. Michael Adler | Google+
