48. THE SECOND HEAD OF THE HYDRA

There are two toxic mechanisms of the fluoroquinolones that explain most of the injuries that they cause:

§ VASCULAR DAMAGE (injury to the small vessels and extracellular matrix)

§ FAULTY NEUROTRANSMISSION (alteration to the transmission of nerve signals)

In this chapter we address the second one, an issue that has been relatively well studied by doctors.

49.NEUROLOGICAL IMPLICATIONS

The longest lasting damage from quinolones is perhaps the neurological alterations. Neurotoxicity is a common feature of all quinolones since such adverse reactions have been described with all quinolone derivatives to date. Some research suggests that quinolones bind to some neuroreceptors (see later) both in the nervous system and in the muscular fascia (contact between nerve and muscle).

TABLE 10. SIMPLISTIC CLASSIFICATION OF NEURO-FLOX-PATHIES

Focal	not associated with floxing
Multifocal	Axonal	Fiber motor	In SEVERE floxings only
		Sensory motor	INTERMEDIATE and SEVERE floxings
		Sensory only	Possible in all floxings
		Small fiber / autonomic	Possible in all floxings
	Demyelinating		uncommon in floxing
NOTE: Multifocal axonal neuropathies are prevalent in floxings.

In other sections of this flox-report, you can find included this simplified table, that classifies the neuro-flox-pathies acording to the areas of the body affected and the type of fibers injured. You will become familiar with the terms used later on. Focal means that only one nerve is affected. Multifocal nerve damage, is used when isolated nerves in different areas are damaged, also called mono-neuropathy multiplex or multi-focal mono-neuropathy (hamstring, ulnar-elbow, ankle, peroneal, sural nerve, cranial nerves...).

As for the cause of the damage, not very conclusive research has been done. Continuing with the vascular hypothesis, maybe the injuries to nerves are secondary (a consequence) to the vasculitic mechanism that would damage the astrocytes in the first instance (see later in this same section).

Neuropathies are a prominent feature of the toxic vasculitides. The reasons for this frequency are not immediately clear. The rich blood supply and the capacity of nerves to function reasonably well with anaerobic (no oxygen) metabolism normally render the nerve relatively resistant to ischemia (disruption of blood supply). That might be a justification for delayed symptoms.

As said, there is no proof that quinolones cause a vasculitic-like neuropathy. Immediate cause of the vasculitic neuropathies is inflammation or deposition of immuno-complexes that eventually harden, thicken, and develop scar tissue, thus decreasing the diameter and impeding blood flow with occlusion of the vasa nervorum, resulting in ischemia of the peripheral nerves that end up damaged or dead. There are other mechanisms, different from vasculitides, that could be the cause. There are several anecdotical reports of patient's recovering from floxings when administered corticoids, that suppress the inmune reaction. However, nothing is mention in those reports about the increased risk of tendon rupture of the concomittant use of quinolones and corticoids.

MEHDI SHAKIBAE ET AL. FREIE UNIVERSITÄT BERLIN, 14195 BERLIN, GERMANY

Furthermore, the pefloxacin-induced tendon injuries were completely inhibited by the coadministration of dexamethasone. At first glance, this finding stands in contrast to the clinical experience that patients undergoing corticosteroid therapy are prone to quinolone-induced tendon disorders, but it could be explained by the fact that patients are usually on continuous therapy, whereas the animals had been treated for a short period only.

There is a group of neuropathies of nerves that do not govern big muscles or limbs, that can be damaged resulting in a vast array of symptoms called peripheral neuropathy. Nearly all the floxed persons have peripheral neuropathy. Peripheral neuropathy describes damage to the peripheral nervous system, the vast communications network that transmits information from the brain and spinal cord (the central nervous system) to every other part of the body and vice versa. Because every peripheral nerve has a highly specialized function in a specific part of the body, a wide array of symptoms can occur when nerves are damaged. Some people may experience temporary numbness, tingling, and pricking sensations (paresthesia), sensitivity to touch, or muscle weakness. Other floxed persons, particularly in severe reactions, may suffer more extreme symptoms, including burning pain (especially at night, very exacerbated by heat), muscle wasting, paralysis, or organ/gland dysfunction. People may become unable to digest food easily, maintain safe levels of blood pressure, sweat normally, or experience normal sexual function.

Some forms of neuropathy involve damage to only one nerve and are called mono-neuropathies that in many cases are difficult to recognize properly and are then diagnosed as normal musculoskeletal injuries. Sometimes two or more isolated nerves in separate areas of the body are affected, called mono-neuritis multiplex. Often though, multiple nerves affecting all limbs are affected, called poly-neuropathy. Toxic drug-induced neuropathy usually involves nerves on both sides of the body, although not always symmetrically (many floxed persons become far more rigid and/or stiff and have more pain on one side), and pain is a common symptom. The neuropathies floxed persons experience are predominantly asymmetrical and they seem to migrate around certain areas of the body, with a marked predilection for lower limbs (large myelinated axons) and distal areas (hands, feet).

In short, quinolones damage both the central and peripheral nervous systems. It is very typical to feel pins and needles sensations, as well as throbbing pains, numbness, trembling, fasciculations (crawling under the skin), tremors, twitching, and neurological pains migrating all over the body. In most severe floxings the associated pain typically does not respond to simple analgesics, and can become chronic and may interfere with sleep (more intense in hot areas of the body) and also be present at rest. Neuropathic pain is difficult to control and can seriously affect emotional wellbeing and overall quality of life. As has been shown earlier: insomnia, nervousness, anxiety, overreactions to stress, anger and anguish are also very common.

The damage is very extensive and symptoms fit well in many neurological sub-diseases, like all kinds of peripheral neuropathies: mono-neuritis multiplex, sensory-motor neuropathies, demyelinating neuropathies, axonal neuropathies, autonomic nerve damage, and many more specific disorders. Central nervous system neuropathies affect many organs like the heart, eyes, brain and intestines.

Floxed persons land powerful blows against their cardiac systems, mucous membranes, skin and peripheral nerves, nearly all are sustained through very severe insults to the nerve functions. The main problem with this toxic neuropathy is that recovery for severe reactions is often only a partial recovery.

50. THE BASIC MISSIONS OF A NERVE CELL

One can find basic texts about neurology that will help to become familar at least with some terms and features of the human nervous system. That will make a lot of easier for you to understand some of the contents of the most interesting research papers that have been published. Here we include some brief explanations about neuron physiology and functions.

Figure 9.

Healthy neuron

Figure 9. (drawing courtesy of a collaborator of the report). Let's suppose a healthy neuron named N4 and depicted in yellow. It receives multiple signals from other neurones' ends (neurons N1, N2 and N3 in blue) and it passes the signal on through its axon (red arrows).

The "head" of the neuron is called the nucleus. The branches of the nucleus are the dendrites. The "trunk" is the axon that is covered by myelin. The other side branches (roots) are the axon terminals.

The signal reaches de branched ends of the axon, where some terminals called "buttons" are placed. These buttons are close to the dendrites of other neurons (for example, neuron N5 in this sketch in purple). We want to know how the yellow nerve cell will transmit the signal received from the blue cells to the purple cell.

The axon has different kinds of neurotransmitters stored in "pouches" vesicles and it releases them according to the signal to be sent (see the amplified detail). The neurotransmitters are released in a free space called synapse. There they are modulated (destroyed, reabsorbed, or metabolized) or left to fit into very precise receptors of the dendrites of the neuron N5, that are specific for each type of transmitter. Once the neurotransmitters have docked in the receptor dendrite, the circuit has been completed and the operational signal has been succesfully transmitted.

This figure has illustrated a nerve-to-nerve connection but there are two basic types of junctions: NERVE-TO-NERVE and NERVE-TO-MUSCLE. For floxed persons is extremely important to know what happens at both kind of junctions, because both types are severely damaged by fluoroquinolones, some in a very long term, irreversible manner.

Explained in precise technical terms: Synaptic transmission refers to the propagation of nerve impulses from one nerve cell to another. This occurs at a specialized cellular structure known as the synapse, a junction at which the axon of the presynaptic neuron terminates at some location upon the postsynaptic neuron. The end of a presynaptic axon, where it is juxtaposed to the postsynaptic neuron, is enlarged and forms a structure known as the terminal button. An axon can make contact anywhere along the second neuron: on the dendrites (a dendritic synapse), the cell body (a somatic synapse) or the axons (an axonal synapse).

Nerve impulses are transmitted at synapses by the release of chemicals called neurotransmitters. As a nerve impulse, or action potential, reaches the end of a presynaptic axon, molecules of neurotransmitter are released into the synaptic space. The neurotransmitters are a diverse group of chemical compounds. The mechanisms by which they elicit responses in both presynaptic and postsynaptic neurons are diverse.

51.THE SPECIFICITY OF THE NERVE-MUSCLE JUNCTION

The above explained nerve-to-nerve junction is one of the two types of nerve signals. The other is the nerve-muscle (neuromuscular) junction. Logically, the nerves that transmit the signals to the muscles, are called motor neurons. The detailed interaction is a bit different from the one depicted in figure 9.

A different type of nerve transmission occurs when an axon terminates on a skeletal muscle fiber, at a specialized structure called the neuromuscular junction. An action potential occurring at this site is known as neuromuscular transmission. At a neuromuscular junction, the axon subdivides into numerous terminal buttons. The particular transmitter in use at the neuromuscular junction is acetylcholine.

In figure 10 (courtesy of a contributor of the flox report) you can see a sketch of a neuromuscular junction. The tip (terminal) of each axon comes into proximity with a muscle fibre, it forms a synapse (small gap) with that fibre. The arrival of a nerve impulse at the neuromuscular junction causes thousands of tiny vesicles (pouches) filled with a specialised neurotransmitter called acetylcholine to be released from the axon tip (terminal) into the synapse.

On the opposite side of the synapse (gap), this acetylcholine then binds to the surface of the muscle fibre at special sites where there are large numbers of acetylcholine receptors (also called nicotinic receptors).

Just like in a synapse between two neurons, when this neurotransmitter (acetylcholine) binds to a receptor, it triggers a new nerve impulse on the muscle fibre membrane. Because of the special way that muscle fibres are structured, this nerve impulse propagates rapidly throughout the fibre and makes it contract.

In short, acetylcholine is a small molecule that acts as a chemical messenger to propagate nerve i