Fundamentals of Neurology: An Illustrated Guide

1. Fundamentals

Microscopic Anatomy of the Nervous system

Elements of Neurophysiology

Elements of Neurogenetics

Image  Microscopic Anatomy of the Nervous System

Neurons are the structural and functional building blocks of the nervous system. This type of cell is specialized for the receptionintegration, and transmission of electrical impulses.

Neurons. The cell body (soma) of the neuron is enclosed by the cell membrane and contains the cell nucleus, mitochondria, endoplasmic reticulum, neurotubules, and neurofilaments (Fig. 1.1). Dendrites are short, more or less extensively branched, cellular processes that conduct afferent impulses toward the cell body. They provide the cell with a much larger surface area than the cell body alone, thereby increasing the area available for intercellular contact and for the deployment of cell membrane receptors. Different types of neurons have different characteristic morphological types of dendrites; those of the cerebellar Purkinje cells, for example, resemble a deer's antlers (Fig. 1.2). The axon is a single cell process, usually longer than a dendrite, which emerges from the cell body at the axon hillock. It conducts efferent impulses away from the cell body to another neuron or an effector organ.

Generally speaking, every neuron has a soma, an axon, and one or more dendrites. The structure and configuration of the nerve cell processes (especially the dendrites) vary depending on the function of the neuron. Thus, neurons can be classified into a number of morphological subtypes (Fig. 1.3).

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Fig. 1.1 Fine structure of a neuron (after Wilkinson, J.L.: Neuroanatomy for Medical Students, 2nd edn, Butterworth–Heinemann, Oxford 1992).

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Fig. 1.2 Cerebellar Purkinje cell (microphotograph). Note the numerous synapses on the dendrites. (Image obtained by Dr. Marco Vecellio, Histological Institute of the University of Fribourg, Switzerland.)

Neuroglia. The neurons constitute the important functional part of the nervous system; they are surrounded by supportive cells, which are collectively called neuroglia. Neuroglial cells of one particular type, the astrocytes, have a starlike morphology. They make contact with nonsynaptic sites on the neuronal surface and possess perivascular foot processes that contact 85 % of the capillaries of the nervous system. Astrocytes ensure an adequate supply of nutrients to the neurons and are an important component of the blood-brain barrier. Other types of supportive cell in the central nervous system include the oligodendrocytesmicroglia, and ependymal cells, and the cells of the choroid plexus.

Myelin sheaths. Axons less than 1 μm in diameter are usually unmyelinated, while thicker axons are sheathed in myelin. The myelin sheath is generated by the “sinking” of an axon into an oligodendrocyte (or, in the peripheral nervous system, a Schwann cell), forming a mesaxon, which consists of a double sheet of cell membrane. The mesaxon wraps around the axon multiple times (Fig. 1.4c). Individual segments of myelin, which can be up to 1 mm long, are separated by the intervening nodes of Ranvier, which play an important role in the transmission of nerve impulses along the axon (p. 4). The “naked” axonal segments at the nodes of Ranvier, are 1–4 μm wide and are only partly covered by processes of the neighboring Schwann cells. They are thus separated from the surrounding endoneural interstitium only by the neuronal cell membrane (neurilemma or axolemma). The nodal axolemma mainly contains voltage-dependent sodium channels, while the internodal segments mainly contain potassium channels.

Synapse. The sites at which neurons transmit impulses to each other are called synapses. Each synapse is composed of a bulblike expansion of the end of an axon, called an axon terminal (or bouton); the synaptic cleft; and the postsynaptic membrane of the receiving neuron or effector organ (Fig. 1.5). Myelinated axons lose their myelin sheath just proximal to the axon terminal. A single neuron can receive synaptic input from one or many axons; the impulses it receives can be either excitatory or inhibitory. An axon can form a synapse onto a cell body, a dendrite, or another axon. Ongoing processes of structural and functional change at the synaptic contacts between nerve cells provide the nervous system with functional adaptability (“plasticity”) even after the individual has reached maturity. Neural impulses are transmitted across synapses by chemical substances called neurotransmitters: some of the more important ones in the central nervous system are dopamine, serotonin, acetylcholine, and γ-aminobutyric acid (GABA). Specialized synapses connect the axons of the peripheral nervous system to effector organs such as muscle cells (motor end plates, p. 263) or glandular cells (p. 280).

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Fig. 1.3 Three types of neurons. The arrows indicate the usual direction of impulse conduction (after Wilkinson, J.L.: Neuroanatomy for Medical Students, 2nd ed, Butterworth–Heinemann, Oxford 1992).

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Fig. 1.4 Peripheral nerve (schematic drawings). a Low magnification reveals the plexuslike structure of the nerve fascicles. b The nerve fascicles (1) are surrounded by a common epineurium (2) composed mainly of fat and connective tissue. Blood vessels (vasa nervorum) lie between the fascicles (3 = arteries, 4 = veins). The fascicles are subdivided by septa derived from the perineurium (5). The endoneurium (6) contains myelinated fibers (7) and capillaries (8). c Electron microscopy reveals the flat perineural cells (9), which are tightly connected to one another by zonulae occludentes (10 = tight junctions) and desmosomes (11). The perineural cell cytoplasm contains many pinocytotic vesicles (12). Within the endoneurium, one can discern myelinated (13) and unmyelinated axons (14), Schwann cells (15), a fibrocyte (16), and a capillary (17 = endothelial cell). The endoneural interstitium contains numerous collagen fibrils (18). The perineural, endothelial, and Schwann cells are surrounded by a basal membrane (19). A mesaxon (20) is formed by the sinking of an axon into a Schwann cell.

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Fig. 1.5 Fine structure of a synapse (diagram after Wilkinson, J.L.: Neuroanatomy for Medical Students, 2nd edn, Butterworth–Heinemann, Oxford 1992).

Image  Elements of Neurophysiology

The resting membrane potential of a neuron or muscle cell can undergo a rapid, transient change, called an action potential, in response to an incoming stimulus or impulse. The action potential is generated by transient changes of ion permeability across the cell membrane. Action potentials and chemical impulse transmission at the synapses are the specific mechanisms used by the nervous system for information transfer.

Neurons are enclosed by a double-layered cell membrane with an inner phospholipid layer and an outer glycoprotein layer. Specialized protein molecules within the cell membrane form channels that are selectively permeable to sodium, potassium, or chloride ions. Some ion channels (e. g., on the postsynaptic membrane) open only when a specific ligand binds to them, e. g., the neurotransmitter molecule that conveys neural impulses from cell to cell. These channels are called ligand-dependent ion channelsVoltage-dependent ion channels, on the other hand, are found mainly on the axonal membrane. They open and close depending on the transmembrane electrical potential.

Resting potential. A difference of electrical potential arises across the neuronal membrane because of the unequal concentrations of ions in the intracellular and extracellular spaces (ICS, ECS) combined with the varying electrical conductivity of the membrane to different types of ion. The resting potential is mainly determined by the ratio of intracellular and extracellular potassium concentration, because, at rest, the membrane is highly permeable to potassium ions and relatively impermeable to sodium ions. The potassium concentration in the ICS is roughly 35 times higher than in the ECS. Thus, potassium ions tend to diffuse out of the cell. The inner surface of the membrane thereby loses positive charges and becomes negatively charged. As negative charge builds up on the inner surface of the membrane, a difference of electrical potential is generated, which opposes further outward flow of potassium ions; negative charge continues to build up until the potential difference exactly cancels out the force arising from the difference in potassium ion concentration. The net effect is that there is no further net transfer of potassium ions across the membrane in either direction and a stable, resting membrane potential is generated, with a value ranging from –60 to –90mV.

Action potential. The sodium ion concentration is roughly 20 times higher in the ECS than in the ICS. Therefore, neurotransmitter-induced opening of ligandsensitive postsynaptic sodium channels is followed by a rapid influx of sodium ions into the cell. The inner surface of the cell membrane becomes positively charged and an action potential is generated whose amplitude and time course are independent of the nature and intensity of the depolarizing impulse (this is the all-or-nothing law of cellular excitation). The transmembrane potential difference reaches a peak positive value ranging from +20 to +50mV. After a brief delay, the potassium channels of the cell membrane become more permeable than at rest, so that a net outflow of potassium ions results. This compensates for the preceding sodium influx and causes repolarization of the membrane to its resting potential. An active sodium pump also participates in this process. Until repolarization is complete, the membrane is temporarily unable to conduct any further impulses; the initial absolute refractory period is followed by a relative refractory period.

Impulse conduction. The axon potential begins at the axon hillock and is then conducted forward along the axonal membrane by the successive opening of voltage-dependent sodium channels. This wave of excitation (local depolarization) travels down the axon at a speed that depends on the thickness of the axon and the thickness of its myelin sheath. The nodes of Ranvier play an especially important role in this process: the isolating myelin sheaths lower the capacitance of the axonal membrane and raise its electrical resistance. The action potentials are therefore initiated only at the nodes, “jumping over” the internodal axon segments (so-called saltatory conduction). Because of this special mechanism, myelinated nerve fibers conduct action potentials much more rapidly than unmyelinated fibers. The normal motor and sensory conduction velocity of peripheral nerves is 50–60 m/s.

Image  Elements of Neurogenetics

Many neurological diseases are caused by genetic defects or tend to arise in the presence of a genetic predisposition. In this section, we will present the basics of both “classical” (Mendelian) inheritance and molecular genetics, as a necessary prerequisite for the understanding of these diseases and for the counseling of affected patients and their families.

General Genetics

The physical characteristics (phenotype) of an individual are determined both by the totality of that individual's genetic information (the genotype) and by environmental influences during gestation and afterward. Genetic information is contained in DNA molecules in the cell nucleus and mitochondria. A segment of DNA containing the information necessary for the synthesis of a protein molecule is called a gene and the totality of the organism's genes is called the genome. The nuclear genes of human beings are contained in 23 pairs of chromosomes—22 pairs of autosomes and one pair of sex chromosomes(gonosomes), which can be either XX (in females) or XY (in males).

Recombination of genetic material. The growth of the organism requires a large number of cell divisions (mitoses). In each mitosis, the nuclear genetic material doubles in amount (replicates) and is then distributed to the two daughter cells, so that each daughter cell, like the original cell, contains a complete (diploid) set of chromosomes. For the purpose of sexual reproduction, however, a reductive cell division (meiosis) occurs, producing egg or sperm cells that contain only a haploid set of chromosomes—i. e., only one of each chromosome (22 autosomes and one sex chromosome), as opposed to the 23 pairs found in all other cells. The union of an egg cell and a sperm cell restores a full (diploid) complement of chromosomes, half of which are derived from the maternal genome and half from the paternal genome.

According to the rules of Mendelian inheritance, maternally-derived and paternally-derived properties (genes) are assorted randomly and independently to the germ cells, and thereby to the offspring. An important limitation of this random and independent assortment comes from the fact that genes located on the same chromosome are ordinarily transmitted together (because entire chromosomes are passed on to the germ cells). Yet, in a particular phase of meiosis, corresponding DNA segments on homologous chromatids can be exchanged with each other (crossing over), producing a new arrangement of genes on the chromatids that take part in the transaction (genetic recombination). The greater the distance between two genes on a chromosome, the more frequently recombination will occur between them.

In addition to these physiological mechanisms leading to change and reassortment of the genetic material (random assortment of maternal and paternal chromosomes in meiosis and fertilization, recombination of genes on homologous chromosomes), spontaneous changes in the genome, called mutations, can also occur. Mutations in the germ line are passed on to the individual's offspring.

Autosomal dominant inheritance. A gene that markedly influences or completely determines the phenotype of the individual in the heterozygous state is called dominant. If the father or mother is heterozygous for a dominant allele, then their child has a 50 % chance of being heterozygous and displaying the corresponding phenotypic trait.

Autosomal recessive inheritance. An autosomal gene that has no effect in the heterozygous state and only manifests itself phenotypically in homozygotes is called recessive. If both the father and the mother are heterozygous for a recessive allele, then 75 % of their progeny will also possess at least one copy of the allele: 50% will be heterozygous and 25% will be homozygous. Only the homozygous offspring will display the corresponding phenotypic trait (e. g., a recessively inherited genetic disease). The heterozygous offspring (“carriers”) will not display the phenotypic trait; neither will the one-quarter of offspring who do not possess the recessive allele.

X-chromosomal inheritance. Males receive an X-chromosome from their mother and a Y-chromosome from their father, while females receive an X-chromosome from both parents. Mothers, therefore, will pass on an X-chromosomal gene to half of their offspring, whether male or female (as long as they are themselves heterozygous for it), while fathers will pass it on to all of their daughters, but not to their sons. Dominantly inherited X-chromosomal diseases affect both males and females; recessively inherited X-chromosomal diseases mainly affect males, striking only the rare females that are homozygous for the disease, i. e., only those who have inherited an X-chromosome with the diseased gene from each of their parents. Any affected male is certain to have received the gene from his mother; as long as his female partner is not a carrier of the disease, all of his daughters will be healthy carriers. Female carriers whose male partners do not have the disease will pass on the disease to 50% of their sons; all of their daughters will be healthy, though half will carry the gene for the disease.

Maternal inheritance of the mitochondrial genome. Mitochondrial DNA is passed on exclusively in the maternal line: mitochondrial genetic diseases are transmitted only by mothers to their children (both male and female), but never by fathers. Mitochondria with mutated DNA can coexist in the same cell with other mitochondria whose DNA is normal. This phenomenon, called heteroplasmia, has no counterpart in the nuclear genome, which is the same in every cell of the body. In mitochondrial genetic diseases, the phenotype, i.e., the extent of damage to the involved cells and tissues, depends on the ratio of mutated to normal mitochondrial DNA and on the number of defective mitochondria that are present.

Mutations are necessary for evolution; without them, the human species would not exist. Yet, adverse mutations can also cause genetic defects and diseases. Mutations can be classified into genomic and intragenic types.

Genomic mutations are of two types, designated as numerical and structural chromosomal aberrations. In the former type of mutation, the number of chromosomes is abnormal (e. g., monosomy, trisomy); in the latter type, the structure of a chromosome is abnormal. Structural aberrations include deletionstranslocations, and inversions of chromosomal segments.

Intragenic mutations involve alterations of the DNA. Within each chromosome, DNA is arranged linearly. DNA segments (genes) that code for amino acid sequences (proteins) are called exons and are found in alternation with noncoding sequences called introns. Exons account for only about 5% of human chromosomal DNA. When the DNA is transcribed into RNA, the primary RNA transcript contains a copy of the introns. These are then spliced out in a second stage of processing, which yields the mature transcript, messenger RNA (mRNA).

Each group of three consecutive nucleotides in the mRNA molecule (called a triplet or codon) codes for an amino in the protein undergoing biosynthesis. “Stop codons” between the exons signal the beginning and end of the gene and thereby determine the length of the protein that is to be synthesized.

Mutations involving the replacement of a DNA nucleotide by a different nucleotide often alter the sense of the codon to which it belongs (missense mutations): the wrong amino acid is inserted into the gene product at this point in protein biosynthesis. The ultimate effect this has on protein function is highly variable. If, however, a nucleotide replacement happens to result in the generation or destruction of a stop codon, an incomplete or excessively long protein will be produced (nonsense mutations). Other mutations involving the insertion of an extra nucleotide into the DNA, or the deletion of a nucleotide, alter the rhythm of nucleotide triplets and are therefore called frame-shiftmutations. These usually cause severe abnormalities of protein structure and function (e. g., Duchenne muscular dystrophy, p. 265).

Expanded repetitive DNA sequences. A further type of mutation of special importance in neurology affects the number of trinucleotides (triplets). Normal human DNA contains a large number of repetitive sequences of trinucleotides, whose presence affects the function and expression of genes. An important group of neurodegenerative diseases is caused by mutations involving abnormally long (expanded) triplet repeat sequences. These diseases are called trinucleotide or triplet repeat diseases. Where the normal repeat sequence might contain only a few triplets, the diseased sequence contains dozens or hundreds. The longer the expansion, the earlier the age of onset of disease, and the more severe its manifestations. The repeat sequences tend to lengthen from one generation to the next, so that the disease tends to appear earlier and earlier (“anticipation”) and to become increasingly severe.

Mutations of mitochondrial DNA impair oxidative metabolism in the mitochondria, causing a number of different types of disease, including mitochondrial encephalomyopathies (p. 272).

Neurogenetics

The triplet diseases are of special relevance to neurology. The neurodegenerative diseases caused by expanded triplet repeats are listed in Table 1.1; their common features are summarized in Table 1.2. Some of the more common inherited mitochondrial diseases are listed in Table 1.3 (for their clinical manifestations, cf. p. 272).

Ever more genetic defects are being identified as the cause of neurological and other diseases. Large tables and books are available for those seeking up-to-date information. Rapid access to the current state of knowledge is best obtained via the Internet. Two useful sites are “Online Mendelian Inheritance in Man” (http://www3.ncbi.nlm.nih.gov/OMIM/) and Medline (http://www4.ncbi.nlm.nih.gov/entrez/query.fcgi).

Genetic Counseling

Many genetic mutations can be detected directly by DNA analysis. The results are highly specific. Thus, many diseases can be diagnosed even before they become symptomatic, so that a long-term prognosis can be given. Sadly, these diseases are generally untreatable and inexorably progressive.

Before any DNA analysis is performed, the treating physician should:

Image perform a meticulous clinical examination,

Image obtain a detailed family history and personally examine the patient's relatives, if possible,

Image inform the patient and his or her relatives in detail about the suspected disease, and

Image explain the consequences of the proposed DNA analysis to them in a readily understandable manner.

A negative DNA analysis can provide relief and free the patient from anxiety. A positive result, on the other hand, may propel the patient into a severe depression, as he or she will then face the certainty of developing an inherited disease, mostly with a grim prognosis, and may not be able to cope with this knowledge. The knowledge of a genetic abnormality may also put a severe stress on a marriage or other partnership. Social problems of yet other kinds may arise, because persons with inherited diseases are, unfortunately, often treated like outcasts in our postindustrial society. They may have troubles in the workplace, not least because they are likely to be uninsurable. For all these reasons, genetic testing generally causes fewer problems if it is performed after the disease has become symptomatic. Asymptomatic children should not be subjected to genetic testing even if their parents ask for it. They should be allowed to decide for themselves whether to undergo testing once they are mature enough to do so and have attained legal majority.

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Many patients and their relatives decide not to undergo testing after being fully informed about their potential genetic disease and the consequences of DNA analysis. In particular, presymptomatic and asymptomatic persons would often rather not find out whether they would develop the disease at some time in the future. A positive test result would destroy their hopes for good health in later life.

If the patient does decide to undergo DNA analysis and then tests positive, the physician should inform the patient and his or her relatives in a personal discussion, with ample time to consider all of the implications. Test results should never be imparted over the telephone or in written form. Patients who have tested positive often need long-term psychotherapy. Nor does the physician–patient relationship end once the test results are given: many patients with hereditary neurological diseases can be greatly helped by continuing psychological support and symptomatic treatment.

Table 1.2 Common features of triplet repeat diseases

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Autosomal dominant or X-chromosomal inheritance

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Onset usually between the ages of 25 and 45

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Gradual progression of disease

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Symmetrical neuronal loss and gliosis in the brain

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Anticipation

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The number of triplet repeats is correlated with the age of onset and the severity of the disease

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The diagnosis can be established by DNA analysis

Table 1.3 Mitochondrial encephalomyopathies

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Progressive external ophthalmopathy (PEO)

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Kearns–Sayre syndrome (KSS)

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Leber hereditary optic neuropathy (LHON)

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Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)

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Leigh disease

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Neuropathy, ataxia, and retinitis pigmentosa syndrome (NARP)

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Myoclonus epilepsy with ragged red fibers (MERRF)


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