Neurology_Adams

Neurology_Adams. A lesion of the dominant thalamus, usually vascular and involving the posterior nuclei, may cause an aphasia, the clinical features of which are not entirely uniform. Typically, there is mutism initially and comprehension is impaired. During the early phases of recovery, spontaneous speech is reduced in amount and is dysfluent; less often, speech is fluent and paraphasic to the point of jargon. Reading and writing may or may not be affected. Characteristically, the patient’s ability to repeat dictated words and phrases is preserved. This configuration has been termed “mixed transcortical aphasia,” a syndrome originally described in bilateral border-zone infarctions or large left-frontal lesions. It may exist in isolation or in combination with the mixed transcortical aphasia. Complete recovery in a matter of weeks is the rule unless the underlying cause is a tumor. Anomia has also been described with ventrolateral thalamic lesions (Ojemann).


Neurology_Adams

Neurology_Adams. Aphasia has also been described frequently with dominant striatocapsular lesions, particularly if they extend laterally into the subcortical white matter of the temporal lobe and insula. The head of the caudate, anterior limb of the internal capsule, or the anterosuperior aspect of the putamen are the structures involved in different patients. The aphasia is characterized by nonfluent, dysarthric, paraphasic speech and varying degrees of difficulty with comprehension of language, naming, and repetition. The lesion is vascular as a rule, and a right hemiparesis is usually associated with it. In general, striatocapsular aphasia recovers more slowly and less completely than thalamic aphasia. These two subcortical aphasias, thalamic and striatocapsular, resemble but are not identical to the Wernicke and Broca types of aphasia, respectively. For further discussion, the reader is directed to the articles of Naeser and of Alexander and their colleagues.


Neurology_Adams

Neurology_Adams. The effects on speech and language of diffuse cerebral disorders, such as delirium tremens and Alzheimer disease, were mentioned in Chaps. 19 and 20. Pathologic changes in parts of the cerebrum other than the perisylvian regions may secondarily affect language function. The lesions that occur in the border zones between major cerebral arteries and effectively isolate perisylvian areas from other parts of the cerebrum fall into this category (see transcortical aphasias). Other examples are the lesions in the mediorbital or superior and lateral parts of the frontal lobes, which impair all motor activity to the point of abulia or akinetic mutism. The mute patient, in contrast to the aphasic one, emits no sounds. If the patient is less severely hypokinetic, his speech tends to be laconic, with long pauses and an inability to sustain a monologue. Extensive occipital lesions will, of course, impair reading, but they also reduce the utilization of all visual and lexical stimuli. Deep


Neurology_Adams

Neurology_Adams. with long pauses and an inability to sustain a monologue. Extensive occipital lesions will, of course, impair reading, but they also reduce the utilization of all visual and lexical stimuli. Deep cerebral lesions, by causing fluctuating states of inattention and disorientation, induce fragmentation of words and phrases and sometimes protracted, uncontrollable talking (logorrhea). The nonaphasic language disorders of the confusional states, emphasized by Geschwind, have already been mentioned.


Neurology_Adams

Neurology_Adams. Also common in global or multifocal cerebral diseases are defects in prosody, both expressive and receptive. These appear in numerous states that affect global cerebral function, such as Alzheimer disease as well as with lesions of the nondominant (right) perisylvian region, as noted in Chap. 21. Severe developmental delay often results in failure to acquire even spoken language, as pointed out in Chaps. 27 and 37. If there is any language skill, it consists only of the understanding of a few simple spoken commands. The subject of developmental dyslexia is discussed in “Developmental Dyslexia” in Chap. 27. Treatment of Aphasia


Neurology_Adams

Neurology_Adams. Treatment of Aphasia The sudden onset of aphasia would be expected to cause great apprehension, but except for cases of pure or almost pure motor disorders of speech, most patients show remarkably little concern. It appears at times that the very lesion that deprives them of speech also causes at least a partial loss of insight into their own disability. This reaches almost a ludicrous extreme in some cases of Wernicke aphasia, in which the patient becomes indignant when others cannot understand his jargon. Nonetheless, as improvement occurs, many patients do become discouraged. Reassurance and a program of speech rehabilitation are the best ways of helping the patient at this stage.


Neurology_Adams

Neurology_Adams. Whether contemporary methods of speech therapy accomplish more than can be accounted for by spontaneous recovery is still uncertain. Most aphasic disorders are caused by vascular disease and trauma, and they are nearly always accompanied by some degree of spontaneous improvement in the days, weeks, and months that follow the stroke or accident. A Veterans Administration Cooperative Study (Wertz et al) has suggested that intensive therapy by a speech pathologist does hasten improvement. Also, Howard and colleagues have shown increased efficacy of word retrieval in a group of chronic stable aphasics treated by two different techniques. More studies of this type, which control for the effects of time, of the patient’s motivation and the interest of family and therapist, are needed. In an interesting personal experiment by Wender, a classicist who had become aphasic, practice of Greek vocabulary and grammar led to recovery in that language, but there was little recovery of her facility


Neurology_Adams

Neurology_Adams. personal experiment by Wender, a classicist who had become aphasic, practice of Greek vocabulary and grammar led to recovery in that language, but there was little recovery of her facility with Latin, which was not similarly exercised.


Neurology_Adams

Neurology_Adams. The methods of language rehabilitation are specialized, and it is advisable to call in a person who has been trained in this field. However, inasmuch as a part of the benefit is also psychologic, an interested family member or schoolteacher can be of help if a speech therapist is not available in the community. Frustration, depression, and paranoia, which complicate some aphasias, may require psychiatric evaluation and treatment. The developmental language disorders of children pose special problems and are considered in Chap. 27.


Neurology_Adams

Neurology_Adams. In general, recovery from aphasia that is due to cerebral trauma is usually faster and more complete than that from aphasia because of stroke. The type of aphasia and particularly its initial severity (extent of the lesion) clearly influence recovery: global aphasia usually improves little, and the same is true of severe Broca and Wernicke aphasias (Kertesz and McCabe). Minimal or “mini” Broca aphasia characterized by slightly effortful and halting speech, recovers quickly. The various dissociative speech syndromes and pure word mutism also tend to improve rapidly and often completely. In general, the outlook for recovery from any particular aphasia is more favorable in a left-handed person than in a right-handed one. Characteristically, in the course of recovery, a severe aphasia of one type may evolve into another type (global into severe Broca; Wernicke, transcortical, and conduction into anomic), which are patterns of recovery that may be attributed to the effects of therapy.


Neurology_Adams

Neurology_Adams. The act of speaking involves a highly coordinated sequence of actions of the respiratory musculature, larynx, pharynx, palate, tongue, and lips. These structures are innervated by the vagal, hypoglossal, facial, and phrenic nerves, the nuclei of which are controlled by both motor cortices through the corticobulbar tracts. As with all movements, those involved in speaking are subject to extrapyramidal influences from the cerebellum and basal ganglia. The act of speaking requires that air be expired in regulated bursts and each expiration must be maintained long enough (by pressure mainly from the intercostal muscles) to permit the utterance of phrases and sentences. The current of expired air is then finely regulated by the activity of the various muscles engaged in speech.


Neurology_Adams

Neurology_Adams. Phonation, or the production of vocal sounds, is a function of the larynx, more particularly the vocal cords. The pitch of the speaking or singing voice depends upon the length and mass of the membranous parts of the vocal cords and can be varied by changing their tension; this is accomplished by means of the intrinsic laryngeal muscles, before any audible sound emerges. The controlled intratracheal pressure forces air past the glottis and separates the margins of the cords, setting up a series of vibrations and recoils. Sounds thus formed are modulated as they pass through the nasopharynx and mouth, which act as resonators. Articulation consists of contractions of the pharynx, palate, tongue, and lips, which interrupt or alter the vocal sounds. Vowels are of laryngeal origin, as are some consonants, but the latter are formed for the most part during articulation; the consonants m, b, and p are labial, l and t are lingual, and nk and ng are guttural (throat and soft palate).


Neurology_Adams

Neurology_Adams. Defective articulation (dysarthria) and phonation (dysphonia) are recognized at once by listening to the patient speak during ordinary conversation or read aloud. Contrived test phrases such as “Methodist Episcopal” or attempts at rapid repetition of lingual, labial, and guttural consonants (e.g., la-la-la-la, me-me-me-me, or k-k-k-k) bring out the particular abnormality. Disorders of phonation call for a precise analysis of the voice and its apparatus.


Neurology_Adams

Neurology_Adams. In pure dysarthria or its most severe representation, anarthria, there is no abnormality of the cortical language mechanisms. The patient is able to understand perfectly what is heard and has no difficulty in reading and writing, although he may be unable to utter intelligible words. This is the strict meaning of being inarticulate. Defects in articulation may be subdivided into several types: lower motor neuron (neuromuscular); spastic (pseudobulbar); rigid (extrapyramidal); cerebellar-ataxic; and hypoand hyperkinetic dysarthrias, each of which is taken up below.


Neurology_Adams

Neurology_Adams. This pattern of speech is caused by weakness or paralysis of the articulatory muscles, the result usually of disease of the motor nuclei of the medulla and lower pons or their intramedullary or peripheral extensions (lower motor neuron paralysis). In advanced forms of this disorder, the shriveled tongue lies inert and fasciculating on the floor of the mouth, and the lips are lax and tremulous. Saliva constantly collects in the mouth because of dysphagia, and drooling is troublesome. Dysphonia, an alteration of the voice to a rasping monotone because of vocal cord paralysis, is often an additional feature. As this condition evolves, speech becomes slurred and progressively less distinct. There is special difficulty in the enunciation of vibratives, such as r, and as the paralysis becomes more complete, lingual and labial consonants are finally not pronounced at all. In the past, bilateral paralysis of the palate, causing nasality of speech, often occurred with diphtheria and


Neurology_Adams

Neurology_Adams. becomes more complete, lingual and labial consonants are finally not pronounced at all. In the past, bilateral paralysis of the palate, causing nasality of speech, often occurred with diphtheria and poliomyelitis, but now it occurs most often with progressive bulbar palsy, a form of motor neuron disease (see “Progressive Bulbar Palsy,” Chap. 39), and with certain other neuromuscular disorders, particularly myasthenia gravis. Bilateral paralysis of the lips, as occurs in the facial diplegia of the Guillain-Barré syndrome or of Lyme disease, interferes with enunciation of labial consonants; p and b are slurred and sound more like f and v. Degrees of both of these abnormalities are also observed in myasthenia gravis, but there are usually additional features of palatal weakness and softening of guttural consonants and nasal air escape.


Neurology_Adams

Neurology_Adams. Diseases that involve the corticobulbar tracts bilaterally, usually a result of vascular, demyelinating, or motor neuron disease (amyotrophic lateral sclerosis), result in the syndrome of spastic bulbar (pseudobulbar) palsy. The patient may have had a clinically inevident vascular lesion at some time in the past, affecting the corticobulbar fibers on one side; however, because the bulbar muscles on each side are innervated by both motor cortices, there may be little or no impairment in speech or swallowing until another stroke occurs involving the other corticobulbar tract at any level. Upon the second stroke, the patient immediately becomes dysphagic, dysphonic, and anarthric or dysarthric, often with paresis of the tongue and facial muscles. This phenomenon has been termed the “bilateral anterior opercular syndrome” and was first recognized by Foix, Chavany, and Marie in 1926. This condition, unlike bulbar paralysis from lower motor neuron involvement, entails no atrophy or


Neurology_Adams

Neurology_Adams. anterior opercular syndrome” and was first recognized by Foix, Chavany, and Marie in 1926. This condition, unlike bulbar paralysis from lower motor neuron involvement, entails no atrophy or fasciculations of the paralyzed muscles; instead, the jaw jerk and other facial reflexes usually become exaggerated, the palatal reflexes are retained or increased, and emotional control is impaired (spasmodic, crying, and laughing—the pseudobulbar affective state described in Chap. 24). Amyotrophic lateral sclerosis is a condition in which the signs of spastic and atrophic bulbar palsy are combined.


Neurology_Adams

Neurology_Adams. When the dominant frontal operculum is damaged, speech may be dysarthric, usually without pseudobulbar impairment in emotional control. In the beginning, with vascular lesions, the patient may be mute; but with recovery or in mild degrees of the same condition, speech is notably slow, thick, and indistinct, much like that of partial bulbar paralysis. The terms cortical dysarthria and cortical anarthria, among many others, have been applied to this disorder, which is more closely related to forms of Broca aphasia than to the dysarthrias being considered in this section. Also, in many cases of partially recovered Broca aphasia and in the “mini-Broca” syndrome, the patient is left with a dysarthria that may be difficult to distinguish from a pure articulatory defect. Careful testing of other language functions, especially writing reveals the aphasic aspect of the defect.


Neurology_Adams

Neurology_Adams. A severe dysarthria that is difficult to classify, but resembles that of cerebellar disease, may occur with a left hemiplegia, usually the result of capsular or right opercular infarction. It tends to improve over several weeks but initially may be so severe as to make speech incomprehensible (Ropper).


Neurology_Adams

Neurology_Adams. In Parkinson and other extrapyramidal diseases associated with rigidity of muscles, one observes a rather different disturbance of articulation, characterized by rapid mumbling and cluttered utterance and slurring of words and syllables. The voice is low-pitched and monotonous, lacking both inflection and volume (hypophonia), and trailing off in volume at the ends of sentences. Words are spoken hastily and run together in a pattern that is almost the opposite of the slowed pattern of spastic dysarthria. In advanced cases, speech is whispered and almost unintelligible. It may happen that the patient finds it impossible to talk while walking but can speak better if standing still, sitting, or lying down. In the extrapyramidal disorder of progressive supranuclear palsy, the dysarthria and dysphonia tend instead to be spastic in nature.


Neurology_Adams

Neurology_Adams. With chorea and myoclonus, speech may also be affected in a highly characteristic way. Talking is loud, harsh, improperly stressed or accented, and poorly coordinated with breathing (hyperkinetic dysarthria). Unlike the defect of pseudobulbar palsy or Parkinson disease, chorea and myoclonus cause abrupt interruptions of the words by superimposition of involuntary inspirations and movements of bulbar muscles. The abnormality has been described as “hiccup speech,” in that the breaks are unexpected, as in singultation. Accompanying grimacing and other movement abnormalities must sometimes be depended upon for diagnosis. The Tourette syndrome of multiple motor and vocal tics is characterized both by startling vocalizations (barking noises, squeals, shrieks, grunting, sniffing, snorting) and by speech disturbances, notably stuttering and the involuntary utterance of obscenities (coprolalia).


Neurology_Adams

Neurology_Adams. Elements of both corticobulbar (spastic) and extrapyramidal speech disturbances are combined in Wilson disease, acquired hepatocerebral degeneration, in Hallervorden-Spatz disease (PKAN, the new and preferable designation based on the kinase that is affected in the disease), and in the form of cerebral palsy called double athetosis. The speech is loud, slow, and labored; it is poorly coordinated with breathing and accompanied by facial contortions and athetotic excesses of tone in other muscles. In diffuse cerebral diseases such as syphilitic general paresis, slurred, tremulous speech is one of the cardinal signs. Ataxic Dysarthria (See Chap. 5)


Neurology_Adams

Neurology_Adams. This condition is a component of acute and chronic cerebellar lesions. It may be observed in multiple sclerosis and various degenerative disorders involving the cerebellum, or as a sequela of anoxic encephalopathy or heat stroke. The principal features are slowness of speech, slurring, monotony, and unnatural separation of the syllables of words. The coordination of speech and respiration is erratic. There may not be enough breath to utter certain words or syllables, and others are expressed with greater force than intended (explosive speech). Scanning dysarthria, speaking metronomically as if scanning poetry for meter, is another distinctive cerebellar pattern and is most often a result of mesencephalic lesions involving the brachium conjunctivum. However, in some cases of cerebellar disease, especially if there is an element of spastic weakness of the tongue from corticobulbar involvement, there may be only a slurring dysarthria, and it is not possible to predict the anatomy of the


Neurology_Adams

Neurology_Adams. especially if there is an element of spastic weakness of the tongue from corticobulbar involvement, there may be only a slurring dysarthria, and it is not possible to predict the anatomy of the lesions from analysis of speech alone. Myoclonic jerks involving the speech musculature may be superimposed on cerebellar ataxia in a number of diseases such as Creutzfeldt-Jakob prion infection and Lance-Adams postanoxic encephalopathy.


Neurology_Adams

Neurology_Adams. This abnormality, characterized by interruptions of the normal rhythm of speech by involuntary repetition and prolongation or arrest of uttered letters or syllables, is a common developmental disorder, discussed in Chap. 27. But as pointed out by Rosenbek and colleagues and by Helm and colleagues, it may appear in patients who are recovering from aphasic disorders and who had never stuttered in childhood. This form of acquired stuttering in adults has some different features from the developmental type in that the repetitions, prolongations, and blocks are not restricted to the initial syllables of words, stuttering occurs at equal frequency for grammatical as for substantive words, there is little adaptation with continued speaking, and is generally unaccompanied by grimacing or associated movements, as happens in some developmental types. These features are discussed in the review by Lundgren and colleagues. Stuttering differs from palilalia, in which there is repetition of a word


Neurology_Adams

Neurology_Adams. movements, as happens in some developmental types. These features are discussed in the review by Lundgren and colleagues. Stuttering differs from palilalia, in which there is repetition of a word or phrase with increasing rapidity, and from echolalia, in which there is an obligate repetition of words or phrases.


Neurology_Adams

Neurology_Adams. In many instances, acquired stuttering is transitory; if it is permanent, according to Helm and associates, bilateral cerebral lesions are present. Nevertheless, we have observed some cases in which only a left-sided, predominantly motor aphasia provided the background for acquired stuttering, and others in which stuttering was an early sign of cerebral glioma originating in the left parietal region. Benson also cites patients in whom stuttering accompanied fluent aphasia. The causative lesion in acquired stuttering may be subcortical and even, as in an exceptional case described by Ciabarra and colleagues, located in the pons. The treatment of Parkinson disease with l-dopa and, occasionally, an acquired cerebral lesion may reactivate developmental stuttering. The latter may explain the emergence of stuttering with oddly situated lesions, such as the aforementioned pontine infarct.


Neurology_Adams

Neurology_Adams. A few points should be made concerning the fourth group of speech disorders, that is, those that are a result of disturbances of phonation. In adolescence, there may be a persistence of the unstable “change of voice” normally seen in boys during puberty. As though by habit, the patient speaks part of the time in falsetto, and the condition may persist into adult life. Its basis is unknown. Probably the larynx is not masculinized, that is, there is a failure in the spurt of growth (length) of the vocal cords that ordinarily occurs in pubertal boys. Voice training has been helpful.


Neurology_Adams

Neurology_Adams. Paresis of respiratory movements, as in myasthenia gravis, Guillain-Barré syndrome, and severe pulmonary disease, may affect the voice because insufficient air is provided for phonation. Also, disturbances in the rhythm of respiration may interfere with the fluency of speech. This is particularly noticeable in extrapyramidal diseases, where one may observe that the patient tries to talk during part of inspiration as noted earlier. Another common feature of the latter diseases is the reduction in volume of the voice (hypophonia) because of limited excursion of the breathing muscles—the patient is unable to shout or to speak above a whisper. Whispering speech is also a feature of advanced Parkinson disease, stupor, and occasionally concussive brain injury and frontal lobe lesions, but strong stimulation may make the voice audible.


Neurology_Adams

Neurology_Adams. With paresis of both vocal cords, the patient can speak only in whispers. Because the vocal cords normally separate during inspiration, their failure to do so when paralyzed may result in an inspiratory stridor. If one vocal cord is paralyzed as a result of involvement of the tenth cranial nerve by tumor, for example, the voice becomes hoarse, low-pitched, rasping, and somewhat nasal in quality. The pronunciation of certain consonants such as b, p, n, and k is followed by an escape of air into the nasal passages. The abnormality is sometimes less pronounced in recumbency and increased when the head is thrown forward. Prolonged tracheal intubation that causes pressure necrosis of the posterior cricoarytenoid cartilage and the underlying posterior branch of the laryngeal nerve is an increasingly common iatrogenic cause.


Neurology_Adams

Neurology_Adams. Various tremor disorders, but especially severe essential tremor, affect the voice by creating an oscillatory effect on the vocal cords (see Chap. 4 for a full discussion). An unusual form of this disease causes a vibrato voice tremor almost in isolation, but most cases occur in the context of severe generalized essential tremor. As noted below, the pitch of voice may increase and simulate spasmodic dysphonia. Only the most severe cases of Parkinson tremor impart a warbling to the voice but this appears to be from vibration of the body and chest.


Neurology_Adams

Neurology_Adams. This is a relatively common condition about which little is known. Spasmodic dysphonia is a better term than the still-appearing spastic dysphonia, as the adjective spastic suggests corticospinal involvement, whereas the disorder is probably of extrapyramidal origin. The authors, like most neurologists, have seen many patients, middle-aged or elderly men and women, otherwise healthy, who lose the ability to speak quietly and fluently. Any attempt to speak results in simultaneous contraction of the speech musculature, so that the patient’s voice is strained and speaking requires an effort. The patient sounds as though he were trying to speak while being strangled. Shouting is easier than quiet speech, and whispering is unaltered. Other actions utilizing approximately the same muscles (swallowing and singing) are usually unimpeded.


Neurology_Adams

Neurology_Adams. Spasmodic dysphonia is usually relatively nonprogressive and occurs as an isolated phenomenon, but we have observed exceptions in which it occurs in various combinations with blepharospasm, spasmodic torticollis, writer’s cramp, or some other type of segmental dystonia. The nature of spasmodic dysphonia is unclear. As a neurologic disorder, it may be akin to writer’s cramp, that is, a restricted dystonia (see Chap. 6). As mentioned just above, we have at times had difficulty differentiating a severe essential tremor of voice from spasmodic dysphonia. They may even coexist (fortunately, the treatments are similar). An anatomic basis for the condition has not been demonstrated, but careful neuropathologic studies have not been made. Glottic spasm, as in tetanus, tetany, and certain hereditary metabolic diseases, results in crowing, stridulous phonation.


Neurology_Adams

Neurology_Adams. Treatment Speech therapists, observing such a patient strain to achieve vocalization, often assume that relief can be obtained by making the patient relax, and psychotherapists believed at first that a search of the patient’s personal life around the time when the dysphonia began would enable the patient to understand the problem and regain a normal mode of speaking. But both these methods have failed without exception. Drugs useful in the treatment of Parkinson disease and other extrapyramidal diseases are practically never effective. Sectioning of one recurrent laryngeal nerve can be beneficial, but recurrence is to be expected. The most effective treatment, comparable to treatment of other segmental dystonias, consists of the injection of 5 to 20 U of botulinum toxin, under laryngoscopic guidance, into each thyroarytenoid or cricothyroid muscle. Relief lasts for several months. Hoarseness and raspiness of the voice is also a result of structural changes in the vocal cords, the


Neurology_Adams

Neurology_Adams. guidance, into each thyroarytenoid or cricothyroid muscle. Relief lasts for several months. Hoarseness and raspiness of the voice is also a result of structural changes in the vocal cords, the result of cigarette smoking, acute or chronic laryngitis, polyps, and laryngeal edema after extubation.


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Neurology_Adams. Alexander MP, Naeser MA, Palumbo CL: Correlation of subcortical CT lesion sites and aphasia profiles. Brain 110:961, 1987. Assal G, Regli F, Thuillard A, et al: Syndrome de l’isolement de la zone du language. Rev Neurol 139:417, 1983. Balter M: “Speech gene” tied to modern humans. Science 297:1105, 2002. Basso A, Taborelli A, Vignolo LA: Dissociated disorders of reading and writing in aphasia. J Neurol Neurosurg Psychiatry 41:556, 1978. Beauvois MF, Saillant B, Meininger V, Lhermitte F: Bilateral tactile aphasia: A tacto-verbal dysfunction. Brain 101:381, 1978. Benson DF: Aphasia, Alexia, and Agraphia. New York, Churchill Livingstone, 1980. Brain R: Speech Disorders. Aphasia, Apraxia and Agnosia. Oxford, Butterworth, 1967. Broca P: Portée de la parole: Ramollisement chronique et destruction partielle du lobe anterieur gauche du cerveau. Paris Bull Soc Anthropol 2:219, 1861.


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Neurology_Adams. Broca P: Portée de la parole: Ramollisement chronique et destruction partielle du lobe anterieur gauche du cerveau. Paris Bull Soc Anthropol 2:219, 1861. Buchman AS, Garron DC, Trost-Cardomone JE, et al: Word deafness: One hundred years later. J Neurol Neurosurg Psychiatry 49:489, 1986. Ciabarra AM, Elkind MS, Roberts JK, Marshall RS: Subcortical infarction resulting in acquired stuttering. J Neurol Neurosurg Psychiatry 69:546, 2000. Critchley M: Aphasiological nomenclature and definitions. Cortex 3:3, 1967. Croisile B, Laurent B, Michel D, et al: Pure agraphia after a deep hemisphere haematoma. J Neurol Neurosurg Psychiatry 53:263, 1990. Damasio AR: Aphasia. N Engl J Med 326:531, 1992. Damasio AR, Damasio H: The anatomic basis of pure alexia. Neurology 33:1573, 1983. Damasio AR, Geschwind N: Anatomical localization in clinical neuropsychology. In: Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol 45. Amsterdam, Elsevier, 1985, pp 7–22.


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Neurology_Adams. Damasio AR, Geschwind N: Anatomical localization in clinical neuropsychology. In: Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology. Vol 45. Amsterdam, Elsevier, 1985, pp 7–22. Damasio H, Damasio AR: Lesion Analysis in Neuropsychology. New York, Oxford University Press, 1989. Damasio H, Damasio AR: The anatomical basis of conduction aphasia. Brain 103:337, 1980. Darby DG: Sensory aprosodia: A clinical clue to lesions of the inferior division of the right middle cerebral artery? Neurology 43:567, 1993. Dejerine J: Contribution a l’étude anatomo-pathologique et clinique des differentes varietés de cécitéverbale. Mem Soc Biol 4:61, 1892. Dronkers NF: A new brain region for coordinating speech articulation. Nature 384:159, 1996.


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Neurology_Adams. Dronkers NF: A new brain region for coordinating speech articulation. Nature 384:159, 1996. Foix, C, Chavany JAE, Marie J. Diplégie facio-linguo-masticatrice d’origine sous-corticale sans paralysie des membres (contribution à l’étude de la localisation des centres de la face du membre supérieur). Revue Neurologique 33:214, 1926. Gardiner AH: The Theory of Speech and Language. Westport, CT, Greenwood Press, 1979. Geschwind N: Disconnection syndromes in animals and man. Brain 88:237, 585, 1965. Geschwind N: Non-aphasic disorders of speech. Int J Neurol 4:207, 1964. Geschwind N: The varieties of naming errors. Cortex 3:97, 1967. Geschwind N: Wernicke’s contribution to the study of aphasia. Cortex 3:449, 1967. Geschwind N, Galaburda AM: Cerebral Dominance: Biological Foundations. Cambridge, MA, Harvard University Press, 1988. Geschwind N, Levitsky W: Human brain: Left-right asymmetries in temporal speech region. Science 161:186, 1968.


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Neurology_Adams. Geschwind N, Levitsky W: Human brain: Left-right asymmetries in temporal speech region. Science 161:186, 1968. Gloning K: Handedness and aphasia. Neuropsychologia 15:355, 1977. Goldstein K: Language and Language Disturbances. New York, Grune & Stratton, 1948, pp 190–216. Goodglass H, Kaplan E: The Assessment of Aphasia and Related Disorders. Philadelphia, Lea & Febiger, 1972. Goodglass H, Quadfasel FA: Language laterality in left-handed aphasics. Brain 77:521, 1954. Greenblatt SH: Alexia without agraphia or hemianopsia. Brain 96:307, 1973. Head H: Aphasias and Kindred Disorders. Cambridge, UK, Cambridge University Press, 1926. Helm NA, Butler RB, Benson DF: Acquired stuttering. Neurology 28:1159, 1978. Howard D, Patterson K, Franklin S: Treatment of word retrieval deficits in aphasia: A comparison of two therapy methods. Brain 108:817, 1985. Joanette Y, Puel JL, Nespoulosis A, et al: Aphasie croisee chez les droities. Rev Neurol 138:375, 1982.


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Neurology_Adams. Joanette Y, Puel JL, Nespoulosis A, et al: Aphasie croisee chez les droities. Rev Neurol 138:375, 1982. Kertesz A: Aphasia and Associated Disorders. Needham Heights, MA, Allyn & Bacon, 1979. Kertesz A: Clinical forms of aphasia. Acta Neurochir (Wien) 56(Suppl):52, 1993. Kertesz A: The Western Aphasia Battery. New York, Grune & Stratton, 1982. Kertesz A, Benson F: Neologistic jargon: A clinicopathologic study. Cortex 6:362, 1970. Kertesz A, McCabe P: Recovery patterns and prognosis in aphasia. Brain 100:1, 1977. Kertesz A, Sheppard A, Mackenzie R: Localization in transcortical sensory aphasia. Arch Neurol 39:475, 1982. Kinsbourne M: Hemispheric Disconnection and Cerebral Function. Springfield, IL, Charles C Thomas, 1974. Kohn, Weigert, 1874. English translation by Eggert GH: Wernicke Works on Aphasia: A Source Book and Review. The Hague, Mouton, 1977. Kurowski KM, Blumstein SE, Alexander M: The foreign accent syndrome: A reconsideration. Brain Lang 54:1, 1996.


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Neurology_Adams. Kurowski KM, Blumstein SE, Alexander M: The foreign accent syndrome: A reconsideration. Brain Lang 54:1, 1996. LeCours H, Lhermitte F: Aphasiology. Eastbourne, UK, Ballière-Tindall, 1989. LeCours H, Lhermitte F: The pure form of the phonetic disintegration syndrome (pure anarthria). Brain Lang 3:88, 1976. Leiner HC, Leiner SL, Dow RS: Cognitive and language functions of the human cerebellum. Trends Neurosci 16:444, 1993. Leischner A: The agraphias. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 4: Disorders of Speech, Perception and Symbolic Behavior. Amsterdam, North-Holland, 1969, pp 141–180. LeMay M, Culebras A: Human brain morphologic differences in the hemispheres demonstrable by carotid angiography. N Engl J Med 287:168, 1972. Levine DN, Mohr JP: Language after bilateral cerebral infarctions: Role of the minor hemisphere in speech. Neurology 29:927, 1979.


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Neurology_Adams. Levine DN, Mohr JP: Language after bilateral cerebral infarctions: Role of the minor hemisphere in speech. Neurology 29:927, 1979. Lundgren K, Helm-Estabrooks N, Klein R: Stuttering following acquired brain damage: A review of the literature. J Neurolingustics 23:447, 2010. Martin N, Saffran EM: A computational account of deep dysphasia: Evidence from a single case study. Brain Lang 43:240, 1992. Milner B, Branch C, Rasmussen T: Evidence for bilateral speech representation in some non-right-handers. Trans Am Neurol Assoc 91:306, 1966. Mohr JP: The vascular basis of Wernicke aphasia. Trans Am Neurol Assoc 105:133, 1980. Mohr JP, Pessin MS, Finkelstein S, et al: Broca aphasia: Pathologic and clinical. Neurology 28:311, 1978. Naeser MA, Alexander MP, Helm-Estabrook N, et al: Aphasia with predominantly subcortical lesion sites. Arch Neurol 39:2, 1982. Ojemann G: Cortical organization of language. J Neurosci 11:2281, 1991.


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Neurology_Adams. Ojemann G: Cortical organization of language. J Neurosci 11:2281, 1991. Price CJ: Functional-imaging studies of the 19th century neurological model of language. Rev Neurol 157:833, 2001. Ropper AH: Severe dysarthria with right hemisphere stroke. Neurology 37:1061, 1987. Rosati G, de Bastiani P: Pure agraphia: A discrete form of aphasia. J Neurol Neurosurg Psychiatry 42:266, 1979. Rosenbek J, Messert B, Collins M, et al: Stuttering following brain damage. Brain Lang 6:82, 1975. Ross ED: The aprosodias. In: Feinberg TE, Farah MJ (eds): Behavioral Neurology and Neuropsychology. New York, McGraw-Hill, 1997, pp 699–717. Roux FE, Dufor O, Giussani C, et al: The graphemic/motor frontal area. Exner’s area revisited. Ann Neurol 66:537, 2009. Schott GD: Mirror writing: Neurological reflections on an unusual phenomenon. J Neurol Neurosurg Psychiatry 78:5, 2007.


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Neurology_Adams. Schott GD: Mirror writing: Neurological reflections on an unusual phenomenon. J Neurol Neurosurg Psychiatry 78:5, 2007. Somerville MJ, Mervis CB, Young EJ, et al: Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353:1694, 2005. Subirana A: Handedness and cerebral dominance. In: Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Vol 4: Disorders of Speech, Perception and Symbolic Behavior. Amsterdam, North-Holland, 1969, pp 284–292. Wender D: Aphasic victim as investigator. Arch Neurol 46:91, 1989. Wernicke C: Der Aphasische Symptomkomplex. Breslau, Germany, 1874. Wertz RT, Weiss DG, Aten JL, et al: Comparison of clinic, home, and deferred language treatment for aphasia: A Veterans Administration Cooperative study. Arch Neurol 43:653, 1986. Willmes K, Poeck K: To what extent can aphasic syndromes be localized? Brain 116:1527, 1993. Wilson SAK: Aphasia. London, Kegan Paul, 1926.


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Neurology_Adams. Willmes K, Poeck K: To what extent can aphasic syndromes be localized? Brain 116:1527, 1993. Wilson SAK: Aphasia. London, Kegan Paul, 1926. Wise RJ, Greene J, Büchel C, Scott SK: Brain regions involved in articulation. Lancet 353:1057, 1999. Yakovlev PI, Rakic P: Patterns of decussation of bulbar pyramids and distribution of pyramidal tracts on the two sides of the spinal cord. Trans Am Neurol Assoc 91:366, 1966. Figure 22-1. Diagram of the brain showing the classic language areas, numbered according to the scheme of Brodmann. The elaboration of speech and language probably depends on a much larger area of cerebrum, indicated roughly by all the shaded zones (see text). Note that areas 41 and 42, the primary auditory receptive areas, are shown on the lateral surface of the temporal lobe but extend to its superior surface, deep within the sylvian fissure.


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Neurology_Adams. Figure 22-2. Cerebral structures concerned with language output and articulation. Broca area; preand postcentral gyri; striatum. Areas 43, 44, and 45 are Brodmann cytoarchitectonic areas. A lesion in any one of the components of this output network (B, C, or S) can produce a mild and transient Broca aphasia. Large lesions, damaging all three components, produce severe, persistent Broca aphasia with sparse, labored, agrammatic speech but well-preserved comprehension. (Illustration courtesy of Andrew Kertesz, MD, FRCP(C).) Chapter 22 Disorders of Speech and Language Disorders of Energy, Mood, and Autonomic and Endocrine Functions CHAPTER 23 Fatigue, Asthenia, Anxiety, and Depression CHAPTER 24 The Limbic Lobes and the Neurology of Emotion CHAPTER 25 Disorders of the Autonomic Nervous System, Respiration, and Swallowing CHAPTER 26 The Hypothalamus and Neuroendocrine Disorders Fatigue, Asthenia, Anxiety, and Depression


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Neurology_Adams. In this chapter, we consider the clinically related phenomena of fatigue, nervousness, irritability, anxiety, and depression. These complaints form the core of a group of “symptom-based” disorders with normal neurologic findings that are nevertheless a large part of medical practice. Although more abstruse than paralysis, sensory loss, seizures, or aphasia, they are no less important, if for no other reason than their frequency. In an audit of a large neurologic practice, anxiety and depressive reactions were the main diagnosis in 20 percent of patients, second only to the symptom of headache (Digon et al). Similarly, in two primary care clinics in Boston and Houston, fatigue was the prominent complaint over 20 percent of patients. Some of these symptoms represent only slight aberrations of function or a heightening or exaggeration of normal reactions to environmental stress or to diseases; others are integral features of the diseases themselves; and still others represent


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Neurology_Adams. of function or a heightening or exaggeration of normal reactions to environmental stress or to diseases; others are integral features of the diseases themselves; and still others represent disturbances of neuropsychiatric function that are components of the diseases described in Chaps. 47 through 49 on psychiatric diseases as viewed through the perspective of neurology.


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Neurology_Adams. Of the symptoms considered in this chapter, fatigue is the most frequent, and the most vague. Fatigue refers to the universally familiar state of weariness or exhaustion resulting from physical or mental exertion. Lassitude has much the same meaning, although in some literature it connotes more of an inability or disinclination to be active, physically or mentally, a “weariness of spirit.” More than half of all patients entering a general hospital register a complaint of fatigability or admit to it when questioned. During World War I, fatigue was such a prominent symptom in combat personnel as to be given a separate place in medical nosology, namely combat fatigue, a term that came to be applied to practically all acute psychiatric disorders occurring on the battlefield. In subsequent wars, it has become a key element of the posttraumatic stress disorders. The common clinical antecedents and accompaniments of fatigue, its significance, and its physiologic and psychologic bases are


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Neurology_Adams. wars, it has become a key element of the posttraumatic stress disorders. The common clinical antecedents and accompaniments of fatigue, its significance, and its physiologic and psychologic bases are best understood by considering the effects of fatigue on the normal individual.


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Neurology_Adams. Fatigue has three basic meanings as experienced in daily life: (1) biochemical and physiologic changes in muscles and a reduced capacity to generate force manifest as weakness, or asthenia; (2) a disorder in behavior, taking the form of a reduced output of work or a lack of endurance; and (3) a subjective feeling of tiredness and the mental discomfort that is associated with such an unnatural state for the individual.


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Neurology_Adams. The decreased productivity and capacity for work, which is a direct consequence of fatigue, has been investigated by industrial psychologists. Their findings demonstrate the importance of motivational factors on work output, whether the effort is of physical or mental type. Quite striking are individual constitutional differences in energy and capacity for work, which vary greatly, just as do differences in temperament. What should be emphasized for neurologic practice is that in the majority of persons complaining of fatigue, one does not find muscle fatigue or weakness. This may be difficult to prove, for many such individuals are disinclined to exert full effort in tests of peak power of muscle contraction or in endurance of muscular activity. Contrariwise, fatigue that is so often correctly attributed to psychologic causes may also be a manifestation of medical diseases such as anemia, occult cancer, and chronic infection of inflammatory processes or of neurologic disorders of


Neurology_Adams

Neurology_Adams. correctly attributed to psychologic causes may also be a manifestation of medical diseases such as anemia, occult cancer, and chronic infection of inflammatory processes or of neurologic disorders of various types.


Neurology_Adams

The Clinical Significance of Fatigue

Neurology_Adams. The Clinical Significance of Fatigue


Neurology_Adams

Neurology_Adams. Patients experiencing lassitude and fatigue have a more or less characteristic way of expressing their symptoms. They say that they are “wiped out, or burned out,” “tired all the time,” “weary,” “exhausted,” or that they have “no energy,” “no ambition,” or “no interest.” They may manifest their condition by showing an indifference to the tasks at hand, by emphasizing how hard they are working, or how stressed they are by circumstances; they may be inclined to lie down or to occupy themselves with trivial tasks. On closer analysis, one observes and hears that many such patients have difficulty initiating activity but also in sustaining it; that is, their endurance is diminished. This condition, of course, is the familiar aftermath of sleeplessness or prolonged mental or physical effort, and, under such circumstances, it is accepted as a normal reaction. When, however, similar symptoms appear without relation to such antecedents, they should be suspected of being the manifestations of


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Neurology_Adams. under such circumstances, it is accepted as a normal reaction. When, however, similar symptoms appear without relation to such antecedents, they should be suspected of being the manifestations of disease.


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Neurology_Adams. The physician’s task is to determine whether the patient is merely suffering from the common physical and mental effects of overwork or from personal life stresses. Overworked, overwrought people are observable everywhere in our society. In addition to fatigue, such persons frequently show irritability, restlessness, sleeplessness, and anxiety, sometimes to the point of panic attacks and a variety of somatic symptoms, particularly abdominal, thoracic, and cranial discomforts. Formerly, society accepted this state in responsible individuals and prescribed the obvious cure, a vacation. Even Charcot made time for regular “cures” during the year, in which he retired to a spa without family, colleagues, or the drain of work. Nowadays, the need to contain this type of stress, to which some individuals are more prone than others, has spawned an industry of meditation, yoga, and similar activities. Individuals with hobbies, nonwork interests, and athletic pursuits seem to be less subject to


Neurology_Adams

Neurology_Adams. are more prone than others, has spawned an industry of meditation, yoga, and similar activities. Individuals with hobbies, nonwork interests, and athletic pursuits seem to be less subject to this problem. A common problem in diagnosis, however, is to ascribe fatigue to overwork when actually it is a manifestation of anxiety or depression, as described just below.


Neurology_Adams

Neurology_Adams. Among chronically fatigued individuals without medical disease, not all deviate enough from normal to justify the diagnosis of anxiety or depression. Many persons, because of circumstances beyond their control, have little motivation and much idle time. They are bored with the monotony of their routine. Such circumstances are conducive to fatigue, just as the opposite, a strong emotion or a new enterprise that excites optimism and enthusiasm will dispel fatigue. Some persons are born with low impulse and energy and become more so at times of stress; they have a lifelong inability to exercise vigorously, to compete successfully, to work hard without exhaustion, to withstand illness or recover quickly from it, or to assume a dominant role in a social group—a “constitutional asthenia” (Kahn’s term). Most of these traits are evident from childhood. These difficulties are not currently framed in these terms because they sound judgmental, but disorders of this type have been known since


Neurology_Adams

Neurology_Adams. term). Most of these traits are evident from childhood. These difficulties are not currently framed in these terms because they sound judgmental, but disorders of this type have been known since antiquity and only vary in name and social context in each era.


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Neurology_Adams. Fatigue as a Symptom of Psychiatric Illness


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Neurology_Adams. The majority of patients who seek medical help for unexplained chronic fatigue and lassitude are found to have anxiety, depression, or both. Formerly this state was called “neurasthenia,” a term introduced by Beard, but because lassitude and fatigue rarely exist as isolated phenomena, the current practice is to label such cases according to the total clinical picture. The usual associated symptoms are anxiety, irritability, depression, insomnia, headaches, dizziness, difficulty in concentrating, reduced sexual drive, and loss (or sometimes increase) of appetite. In one series, 85 percent of persons admitted to a general hospital and seen in consultation by a psychiatrist for the chief complaint of chronic fatigue were diagnosed, finally, as having anxious depression or a chronic anxiety state. In a subsequent study, Wessely and Powell found similarly that 72 percent of patients who presented to a neurologic center with unexplained chronic fatigue proved to have a psychiatric disorder,


Neurology_Adams

Neurology_Adams. In a subsequent study, Wessely and Powell found similarly that 72 percent of patients who presented to a neurologic center with unexplained chronic fatigue proved to have a psychiatric disorder, most often a depressive illness.


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Neurology_Adams. Several features are common to the psychiatric group with fatigue. Tests of peak muscle power on command, with the patient exerting full effort, reveal no weakness. The sense of fatigue may be worse in the morning. The fatigue is worsened by mild exertion and relates more to some activities than to others. Inquiry may disclose that the symptom was first experienced in temporal relation to a grief reaction, a surgical procedure, physical trauma such as an automobile accident, or a medical illness such as myocardial infarction. The feeling of fatigue interferes with both mental and physical activities; the patient is easily worried, is “full of complaints,” and finds it difficult to concentrate in attempting to solve a problem or to read a book, or in carrying on a complicated conversation. Also, sleep is disturbed, with a tendency to early morning waking, so that such persons are at their worst in the morning, both in spirit and in energy output. Their tendency is to improve as the day


Neurology_Adams

Neurology_Adams. Also, sleep is disturbed, with a tendency to early morning waking, so that such persons are at their worst in the morning, both in spirit and in energy output. Their tendency is to improve as the day wears on, and they may even feel fairly normal by evening. Severe fatigue that causes the patient consistently to go to bed right after dinner and makes all mental activity effortful should suggest an associated depression. It may be difficult to decide whether the fatigue is a primary manifestation of the disease or secondary to a lack of interest.


Neurology_Adams

Neurology_Adams. Not unexpectedly, fatigue and intolerance of exercise (i.e., fatigue with even mild exertion) are prominent manifestations of certain muscle disease. The most prominent such disorder displaying fatigue and lack of muscular endurance is myasthenia gravis, in which progressively less power is developed with each muscle contraction. In addition to myasthenia gravis, the classes of myopathy in which weakness, inability to sustain effort, and excessive fatigue are notable include the muscular dystrophies, congenital myopathies, other disorders of neuromuscular transmission (Lambert-Eaton syndrome), toxic myopathies (e.g., from cholesterol-lowering drugs), some of the glycogen storage myopathies, and mitochondrial myopathies. One type of glycogen storage disease, McArdle phosphorylase deficiency, is exceptional in that fatigue and weakness are accompanied by pain and sometimes by cramps and contracture. Another such process, acid maltase deficiency, is at times associated with


Neurology_Adams

Neurology_Adams. deficiency, is exceptional in that fatigue and weakness are accompanied by pain and sometimes by cramps and contracture. Another such process, acid maltase deficiency, is at times associated with disproportionate weakness and fatigue of respiratory muscles, which leads to dyspnea and retention of carbon dioxide. The characteristics of these diseases are presented in the chapters on muscle disease. Further comments on muscular fatigue can be found in Chap. 45.


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Neurology_Adams. Fatigue of varying degree is also a regular feature of all diseases that are marked by denervation of muscle and loss of muscle fibers. Fatigue in these cases is a result of the excessive work imposed on the remaining intact muscle (overwork fatigue). This is most characteristic of amyotrophic lateral sclerosis and the postpolio syndrome, but it also occurs in patients as they are recovering from Guillain-Barré syndrome and in those with chronic polyneuropathy.


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Neurology_Adams. Not surprisingly, many neurologic diseases that are characterized by difficulty engaging the muscles (Parkinson disease is the main example). Muscles partially paralyzed by a stroke feel tired and may cause an overall fatigue state. The distinguished neuroanatomist A. Brodal gave an interesting account of his own stroke and its effects on muscle power. Fatigue is often a major complaint of patients with multiple sclerosis; its cause is unknown, although the effect of cytokines circulating in the cerebrospinal fluid has been postulated. The depression that follows stroke or myocardial infarction frequently presents with the complaint of fatigue rather than other signs of mood disorder. Inordinate fatigue is a common complaint among patients with postconcussive syndrome (see Chap. 34). These central fatigue states and their possible mechanisms, almost all speculative, have been discussed by Chaudhuri and Behan.


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Neurology_Adams. Many states of disordered autonomic function in which static or orthostatic hypotension are features are also associated with a fatigue state. Whether there is in addition a type of central autonomic (hypothalamic) fatigue, aside from the endocrine changes discussed below, is uncertain, but such an entity seems plausible and has been included in models of the illness currently called chronic fatigue syndrome.


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Neurology_Adams. A wide variety of medications and other therapeutic agents, particularly when first administered, may induce fatigue. The main offenders in this respect are antihypertensive drugs, especially beta-adrenergic blocking agents, antiepileptic medications, antispasticity drugs, anxiolytics, chemotherapy and radiation therapy and, paradoxically, some antidepressant and antipsychotic drugs. Introduction of these medications in gradually escalating doses may obviate the problem, but just as often, an alternative medicine must be chosen. The administration of beta-interferon for the treatment of multiple sclerosis (and alpha-interferon for other diseases) induces fatigue of varying degree. Surgeons and nurses can testify to fatigue that comes with exposure to anesthetics in inadequately ventilated operating rooms. Similarly, fatigue and headache may result from exposure to carbon monoxide or natural gas in homes with furnaces in disrepair or from leaking gas pipes, but this is also a frequent


Neurology_Adams

Neurology_Adams. operating rooms. Similarly, fatigue and headache may result from exposure to carbon monoxide or natural gas in homes with furnaces in disrepair or from leaking gas pipes, but this is also a frequent delusion in anxious, depressed, or demented patients.


Neurology_Adams

Neurology_Adams. The sleep apnea syndrome is an important and often overlooked cause of fatigue and daytime drowsiness. In overweight men who snore loudly and need to nap frequently, testing for sleep apnea is indicated (this subject was taken up in Chap. 18). Correcting the obstructive apnea that underlies this condition leads to a dramatic reduction in fatigue. The same holds for patients who have neuromuscular diseases that affect the diaphragm and other respiratory muscles.


Neurology_Adams

Neurology_Adams. Acute or chronic infection is an important cause of fatigue. Everyone has at some time or other sensed the abrupt onset of exhaustion, a tired ache in the muscles, or an inexplicable listlessness, only to discover later that he was “coming down with the flu.” Chronic infections such as hepatitis, tuberculosis, brucellosis, infectious mononucleosis, HIV, and bacterial endocarditis may not be evident immediately but should be suspected when fatigue is a new symptom and disproportionate to other symptoms such as mood change, nervousness, and anxiety. Whether a chronic form of Lyme disease is responsible for chronic fatigue, as often imputed, is uncertain at best. Often, fatigue begins with an obvious infection (such as influenza, hepatitis, or infectious mononucleosis), but persists for several weeks after the overt manifestations of infection have subsided; it may then be difficult to decide whether the fatigue represents the lingering effects of the infection or is due to


Neurology_Adams

Neurology_Adams. for several weeks after the overt manifestations of infection have subsided; it may then be difficult to decide whether the fatigue represents the lingering effects of the infection or is due to psychologic-asthenic symptoms during convalescence. This difficult problem is discussed below. Patients with systemic lupus, Sjögren syndrome, or polymyalgia rheumatica may complain of severe fatigue; in the last of these, fatigue may be the initial and a profound symptom.


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Neurology_Adams. Metabolic and endocrine diseases of various types may cause inordinate degrees of lassitude and fatigue. Sometimes there is, in addition, a true muscular weakness. In persons with hypothyroidism with or without frank myxedema, lassitude and fatigue are frequent complaints, as are muscle aches and joint pains. In Addison, Sheehan, and Simmonds diseases, fatigue may dominate the clinical picture. Aldosterone deficiency is another established cause of chronic fatigue. Fatigue may also be present in patients with hyperthyroidism, but it is usually less troublesome than nervousness. Uncontrolled diabetes mellitus is accompanied by excessive fatigability, as are hyperparathyroidism, hypogonadism, and Cushing disease. Fatigue as a feature of vitamin B12 deficiency, as stated in many textbooks, has not been evident in the cases with mild deficiency that we have observed.


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Neurology_Adams. Reduced cardiac output and diminished pulmonary reserve are important causes of breathlessness and fatigue, which are brought out by mild exertion. Anemia, when severe, is another cause, probably predicated on a similar inadequacy of oxygen supply to tissues. Mild grades of anemia are usually asymptomatic, and tiredness is still far too often ascribed to it. An occult malignant tumor, for example, pancreatic, hepatic, or gastric carcinoma, may announce itself by inordinate fatigue. In patients with metastatic carcinoma, and especially lymphoma, leukemia, or multiple myeloma, fatigue is a usual and prominent symptom. Uremia is accompanied by fatigue; the associated anemia may play a role. Any type of nutritional deficiency may, when severe, cause lassitude; in its early stages, this may be the chief complaint. Weight loss and a history of alcoholism and dietary inadequacy provide the clues to the nature of the illness.


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Neurology_Adams. Pregnancy causes fatigue, which may be profound in the later months. To some extent the underlying causes, including the work of carrying excess weight and an anemia, are obvious; but if excessive weight gain and hypertension are associated, preeclampsia should be suspected.


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Neurology_Adams. A particularly difficult problem arises in the patient who complains of severe fatigue for many months or even years after a bout of infectious mononucleosis or some other viral illness. This has been appropriately called the postviral fatigue syndrome. The majority of patients are women between 20 and 40 years of age, but there are undoubtedly young men with the same illness. A few such patients had been found to have unusually high titers of antibody to Epstein-Barr virus (EBV), which suggested a causal relationship and gave rise to terms such as the chronic infectious mononucleosis or chronic EBV syndrome (Straus et al). However, subsequent studies made it clear that a majority of patients with complaints of chronic fatigue have neither a clear-cut history of infectious mononucleosis nor serologic evidence of this or another infection (Straus; Holmes et al). In some of these patients, the fatigue state has allegedly been associated with obscure immunologic abnormalities similar to


Neurology_Adams

Neurology_Adams. serologic evidence of this or another infection (Straus; Holmes et al). In some of these patients, the fatigue state has allegedly been associated with obscure immunologic abnormalities similar to those attributed (spuriously) to silicone breast implants or minor trauma. The currently fashionable designation for these abstruse states of persistent fatigue is the chronic fatigue syndrome (see Dawson and Sabin).


Neurology_Adams

Neurology_Adams. Some perspective is provided by the recognition that a malady of this nature, under many different names, has long pervaded western society, as described by Shorter in an informative history of the chronic fatigue syndrome. The attribution of fatigue to viral or Lyme infection and to ill-defined immune dysfunction are only the latest in a long line of putative explanations. At various times, even in our recent memory, colitis and other forms of bowel dysfunction, spinal irritation, hypoglycemia, brucellosis, and chronic candidiasis, multiple chemical sensitivity, retroviral infection, environmental allergies and recently, gluten sensitivity and minimally low testosterone among others, have been proposed without basis as causes of fatigue. At times, these spurious associations have only served to marginalize the disease and patients who suffer from it.


Neurology_Adams

Neurology_Adams. The current criteria for the diagnosis of chronic fatigue syndrome are the presence of persistent and disabling fatigue for at least 6 months, coupled with an arbitrary number (6 or 8) of persistent or recurrent somatic and neuropsychologic symptoms including low-grade fever, cervical or axillary lymphadenopathy, myalgias, migrating arthralgias, sore throat, forgetfulness, headaches, difficulties in concentration and thinking, irritability, and sleep disturbances (Holmes et al). A number of such patients in our experience have complained of paresthesias in the feet or hands. On close questioning, many of these sensations prove to be odd, particularly numbness in the bones or muscles or fluctuating patches of numbness or paresthesia on the chest, face, or nose. Unusual descriptions may be given if the patient is allowed adequate time to describe the symptoms. A few have reported blurred or “close to” double vision; in neither case are there physical findings to corroborate the sensory


Neurology_Adams

Neurology_Adams. given if the patient is allowed adequate time to describe the symptoms. A few have reported blurred or “close to” double vision; in neither case are there physical findings to corroborate the sensory experiences. With regard to headache, it is worth consulting the section in Chap. 9 regarding “recent onset daily headache,” an unusual entity in which severe bilateral headache without distinguishing features arises very rapidly, sometimes after a viral illness, is unremitting for months or longer and resistant to treatment.


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Neurology_Adams. There is a common association with the similarly obscure entity of fibromyalgia, consisting of neck, shoulder, and paraspinal pain and point tenderness, as described in Chaps. 10 and 45. Despite these complaints, the patient may look surprisingly well and the neurologic examination is normal. The term for this same chronic fatigue entity, myalgic encephalomyelitis, is preferred in Great Britain and captures the association between the two syndromes.


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Neurology_Adams. In a large group of patients who were studied 6 months after viral infections, Cope and colleagues found that none of the features of the original illness was predictive of the development of chronic fatigue; however, a previous history of fatigue or psychiatric problems, and an indefinite diagnosis were often associated with persistent disability. In one study of more than 1,000 patients who were observed for 6 months following an infective illness, the chronic fatigue syndrome was no more frequent than in the general population (Wessely et al). One thing is clear to the authors: that applying the label of chronic fatigue syndrome in susceptible individuals tends to perpetuate this state.


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Neurology_Adams. Complaints of muscle weakness are also frequent among such patients, but Lloyd and coworkers, who studied their neuromuscular performance and compared them with control subjects, found no difference in maximal isometric strength or endurance in repetitive submaximal exercise and no change in intramuscular acidosis, serum creatine kinase (CK) levels, or depletion of energy substrates. These individuals share with depressed patients a subnormal response to cortical magnetic motor stimulation after exercise (Samii et al), which can be said to match their symptoms of reduced endurance but otherwise is difficult to interpret. In a small number of affected persons, a chronic but usually mild hypotension, elicited with tilt-table testing and reversed by mineralocorticoids, has been proposed as a cause of chronic fatigue (Rowe et al). Electromyography and nerve conduction studies are typically normal, as is the spinal fluid, but the electroencephalogram (EEG) may be mildly and nonspecifically


Neurology_Adams

Neurology_Adams. cause of chronic fatigue (Rowe et al). Electromyography and nerve conduction studies are typically normal, as is the spinal fluid, but the electroencephalogram (EEG) may be mildly and nonspecifically slowed. Batteries of psychologic tests have disclosed variable impairments of cognitive function, misinterpreted by advocates of the “organic” nature of the syndrome as proof of some type of encephalopathy. Similarly, sensory complaints such as paresthesias and numbness are common, sometimes in one region of the body but little objective evidence of a neuropathy or myelopathy can be found.


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Neurology_Adams. Having oriented the above discussion to imply that many cases of chronic fatigue have a psychologic, or asthenic basis, it should be emphasized that previously healthy individuals, may have persistent fatigue for years after a severe febrile viral infection. Most of these cases, in our experience, have arisen suddenly, mostly in adolescents and young men, and less often women, who experience overwhelming fatigue during a well-documented and prolonged viral infection. They continue to take interest in activities in which they are able to participate, do not show anxiety or major depressive symptoms, and have the best prognosis, although complete recovery may take up to 5 years. Often these patients are able to define the date on which the illness began. The term postviral fatigue state is most appropriate for this group. Impressive in some of our cases have been severe headaches and orthostatic hypotension, with wide swings in blood pressure resulting in syncope as well as intermittent


Neurology_Adams

Neurology_Adams. appropriate for this group. Impressive in some of our cases have been severe headaches and orthostatic hypotension, with wide swings in blood pressure resulting in syncope as well as intermittent hypertension. Alcohol intolerance may develop. It would seem that the more ambiguous and less-severe cases of chronic fatigue, particularly those with fibromyalgia, may have a different basis, but this cannot be stated with certainty.


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Neurology_Adams. At the present time, the status of the chronic fatigue syndrome is undetermined. The possibility of an obscure endocrine, metabolic or immunologic derangement secondary to a viral infection cannot be dismissed, as discussed by Swartz, but the majority of cases lack such a history and no evidence of a virologic cause has so far held up. Certainly, high levels of cytokines, such as occur after many types of illness and with cancer, and some of the numerous endocrine aberrations are capable of causing fatigue and lethargy. From a neurologic perspective, the hypothalamus is the structure most implicated by the loss of endurance and the presence of associated symptoms such as orthostatic intolerance, tachycardia and some of the endocrine changes enumerated later in the chapter. Treatment, largely unsatisfactory, is discussed further on. Differential Diagnosis of Fatigue


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Neurology_Adams. Differential Diagnosis of Fatigue If one looks critically at patients who seek medical help because of incapacitating exhaustion, lassitude, and fatigability, it is evident that the most commonly overlooked diagnoses are anxiety and depression as described in Chap. 47. The correct conclusion can usually be reached by keeping these illnesses in mind as one elicits the history from patient and family. Difficulty arises when symptoms of the psychiatric illness are so inconspicuous as not to be appreciated; one comes then to suspect the diagnosis only by having eliminated the common medical causes. Repeated observation may bear out the existence of an anxiety state or gloomy mood. Reassurance in combination with a therapeutic trial of antidepressant drugs may suppress symptoms of which the patient was barely aware, thus clarifying the diagnosis. The best that can be done is to assist the patient in adjusting to the adverse circumstances that have brought him under medical surveillance.


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Neurology_Adams. In intractable cases, tuberculosis, brucellosis, Lyme disease, hepatitis, bacterial endocarditis, mycoplasmal pneumonia, HIV, EBV, cytomegalovirus (CMV), coxsackie B, and other viral infections, and malaria, hookworm, giardiasis, and other parasitic infections need to be considered in the differential diagnosis, and an inquiry made for their characteristic symptoms, signs, and when appropriate, laboratory findings; however, such infections are infrequently found. There should also be a search for anemia, renal failure, chronic inflammatory disease such as temporal arteritis and polymyalgia rheumatica (sedimentation rate); an endocrine survey (thyroid, calcium, and cortisol and testosterone levels) and, in appropriate cases, an evaluation for an occult tumor are also in order in obscure cases. It must be remembered that chronic intoxication with alcohol, barbiturates, or other sedative drugs, some of which are given to suppress nervousness or insomnia, may contribute to fatigability.


Neurology_Adams

Neurology_Adams. It must be remembered that chronic intoxication with alcohol, barbiturates, or other sedative drugs, some of which are given to suppress nervousness or insomnia, may contribute to fatigability. The rapid and recent onset of fatigue should always suggest the presence of an infection, a disturbance in fluid balance, gastrointestinal bleeding, or rapidly developing circulatory failure of either peripheral or cardiac origin. The features that suggest sleep apnea have been mentioned above and are discussed further in Chap. 18.


Neurology_Adams

Neurology_Adams. Finally, it bears repeating fatigue must be distinguished from genuine muscular weakness. The demonstration of reduced power, reflex changes, fasciculations, and atrophy sets the case analysis along different lines, bringing up for particular consideration diseases of the peripheral nervous system or of the musculature. Rare, difficult-to-diagnose diseases that cause inexplicable muscle weakness and exercise intolerance are otherwise inevident hyperthyroidism, hyperparathyroidism, ossifying hemangiomas with hypophosphatemia, some of the periodic paralyses, hyperinsulinism, disorders of carbohydrate and lipid metabolism, and the mitochondrial myopathies, all of which are discussed in later chapters of the book on disease of muscle. Treatment of Fatigue


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Neurology_Adams. It has been our impression that most patients with ongoing complaints of very low energy without a clearly preceding febrile infection from the outset and without one of the medical illnesses associated with fatigue, have elements of depression. They are probably best treated with gradually increasing exercise levels and perhaps with antidepressant medication, although this regimen has not always been successful. There are reports of success in treating these patients with mineralocorticoids (predicated on the above-mentioned orthostatic intolerance), estradiol patches, hypnosis, and a variety of other medical and nonmedical treatments. Cognitive and behavioral therapies have been summarized in the Effective Health Care report by Bagnall and colleagues from the National Health Service Centre for Reviews and Dissemination and in the extensive review by Chambers and colleagues, neither of which came to a firm conclusion about the effects of treatment, but acknowledged that cognitive


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Neurology_Adams. Centre for Reviews and Dissemination and in the extensive review by Chambers and colleagues, neither of which came to a firm conclusion about the effects of treatment, but acknowledged that cognitive behavioral therapy and graded exercise therapy may be of value. A few patients with chronic fatigue exhibit the psychologic disorder related to litigation (“compensation neurosis”). Noteworthy is the frequency with which a similar syndrome has become the basis of court action against employers or claims against the government, as in the “building-related illness” (formerly “sick-building syndrome”). As alluded to earlier, attribution of fatigue to Lyme disease and obscure infections or allergies should be made cautiously if there is no firm evidence.


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Neurology_Adams. NERVOUSNESS, ANXIETY, STRESS, The world is full of nervous, tense, apprehensive, and worried people. The stresses of contemporary society are often blamed for their plight. The poet W.H. Auden referred to his era as “the age of anxiety,” and little has changed since then. Medical historians have identified comparable periods of pervasive anxiety dating back to the time of Marcus Aurelius and Constantine, when societies were undergoing rapid and profound changes, and individuals were assailed by an overwhelming sense of insecurity, personal insignificance, and fear of the future (Rosen).


Neurology_Adams

Neurology_Adams. Like fatigue, nervousness, irritability, and anxiety are among the most frequent symptoms encountered in office and hospital practice. A British survey found that more than 40 percent of the population, at one time or another, experienced symptoms of severe anxiety, and approximately 5 percent suffered from lifelong anxiety states (Lader). The latter is difficult to distinguish from what is currently termed generalized anxiety disorder, a state of constant worry discussed further on. The vast amount of antianxiety medication and alcohol that is consumed in our society would tend to corroborate these figures.


Neurology_Adams

Neurology_Adams. Of course, any person facing a challenging or threatening task for which he may feel unprepared and inadequate experiences some degree of nervousness and anxiety. Anxiety is then not abnormal, and the alertness and attentiveness that accompany it may actually improve performance up to a point. Barratt and White found that mildly anxious medical students performed better on examinations than those lacking in anxiety. As anxiety increases, so does the standard of performance, but only to a point, after which increasing anxiety causes a rapid decline in performance (Yerkes-Dodson law).


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Neurology_Adams. If worry or depression stands in clear relation to serious economic reverses or loss of a loved one, the symptom is also usually accepted as normal, but no less worthy of emotional support. Only when it is excessively intense or prolonged or when accompanying visceral derangements are prominent do anxiety and depression become matters of medical concern. Admittedly, the line that separates normal emotional reactions and pathologic ones is not sharp. Chapter 48 deals with these matters more fully.


Neurology_Adams

Neurology_Adams. There is no unanimity as to whether symptoms of nervousness, irritability, anxiety, and fear comprise a single emotional reaction, varying only in its severity or duration, or a group of discrete reactions, each with distinctive clinical features. In some writings, anxiety is classified as a form of subacute or chronic fear but there is reason to question this assumption. Anxious patients, when frightened under experimental conditions, state that the fear reaction differs in being more overwhelming. The exceedingly frightened person is “frozen,” unable to act or to think clearly, and his responses are automatic and sometimes irrational. The fear reaction is characterized by overactivity of both the sympathetic and parasympathetic nervous systems, and the parasympathetic effects (bradycardia, sphincteric relaxation) may predominate, unlike anxiety, in which sympathetic effects are the more prominent ones. Long ago, Cicero distinguished between an acute and transient attack of fear


Neurology_Adams

Neurology_Adams. sphincteric relaxation) may predominate, unlike anxiety, in which sympathetic effects are the more prominent ones. Long ago, Cicero distinguished between an acute and transient attack of fear provoked by a specific stimulus (angor) and a protracted state of fearfulness (anxietas). This distinction was elaborated by Freud, who regarded fear as an appropriate response to a sudden, unexpected external threat and anxiety as a neurotic maladjustment.


Neurology_Adams

Neurology_Adams. Less readily distinguishable from anxiety is the complaint of nervousness. By this vague term, the layperson usually refers to a state of restlessness, inner tension, uneasiness, apprehension, irritability, or hyperexcitability. Unfortunately, the term may have a wide range of other connotations, such as a distressing hallucination or paranoid idea, a frankly hysterical outburst, or even tics or tremulousness. Obviously, a careful inquiry as to what the patient means in complaining of nervousness is always a necessary first step in the analysis.


Neurology_Adams

Neurology_Adams. We use the term anxiety to denote an emotional state characterized by subjective feelings of nervousness, irritability, uneasy anticipation, and apprehension, often but by no means always with a definite topical content and the physiologic accompaniments of strong emotion, that is, one or more of the symptoms of breathlessness, tightness in the chest, choking sensation, palpitation, increased muscular tension, dizziness, trembling, sweating, and flushing. The vasomotor and visceral accompaniments are mediated through the autonomic nervous system, particularly its sympathetic part, and involve also the thyroid and adrenal glands.


Neurology_Adams

Neurology_Adams. The symptoms of anxiety may be manifest either in acute episodes, each lasting several minutes or up to an hour, or as a protracted state that may last for weeks, months, or years. In the panic attack, the patient is suddenly overwhelmed by feelings of apprehension, or a fear that he may lose consciousness and die, have a heart attack or stroke, lose his reason or self-control, become insane, or commit some horrible crime. These experiences are accompanied by a series of physiologic reactions, mainly sympathoadrenal hyperactivity, resembling the “fight-or-flight” reaction. Breathlessness, a feeling of suffocation, dizziness, sweating, trembling, palpitation, and precordial or gastric distress are typical but not invariable physical accompaniments. As a persistent and less-severe state, the patient experiences fluctuating degrees of nervousness, palpitation or excessive cardiac impulse, shortness of breath, light-headedness, faintness, easy fatigue, and intolerance of physical


Neurology_Adams

Neurology_Adams. the patient experiences fluctuating degrees of nervousness, palpitation or excessive cardiac impulse, shortness of breath, light-headedness, faintness, easy fatigue, and intolerance of physical exertion.


Neurology_Adams

Neurology_Adams. Attacks tend to occur during periods of relative calm and in nonthreatening circumstances. Usually, the apprehension and physical symptoms escalate over a period of minutes to an hour and then abate over 20 to 30 min, leaving the patient tired, weak, and perplexed. The dramatic symptoms of the panic attack have usually abated by the time the patient reaches a doctor’s office or an emergency department, but the blood pressure may still be elevated, and there may be tachycardia. Otherwise, the patient looks remarkably collected. Often, discrete anxiety attacks and persistent states of anxiety merge with one another. The fear of further attacks leads many patients, particularly women, to become agoraphobic and homebound, fearing public places, especially if alone.


Neurology_Adams

Neurology_Adams. Because panic is a common disorder, affecting 2 to 4 percent of the population at some time in their lives as cited by Roy-Byrne and colleagues, and the symptoms mimic acute neurologic disease, the neurologist is often called upon to distinguish panic attacks from temporal lobe seizures or from vertiginous disorders. Except for the occasional inability of the patient to think or articulate clearly during a panic attack, the manifestations of epilepsy are quite different. Practically never is consciousness lost during a panic attack. If dizziness predominates in the attacks, there may be concern about vertebrobasilar ischemia or labyrinthine dysfunction (see Chap. 14). Vertigo from any cause is accompanied by many of the autonomic symptoms displayed during a panic attack, but careful questioning in the latter will elicit the characteristic apprehension, breathlessness, and palpitations, and the absence of ataxia or other neurologic signs.


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Neurology_Adams. Recurrent panic attacks and chronic anxiety have a familial aspect, with one-fifth of first-degree relatives affected and a high degree of concordance in monozygotic twins. The panic symptoms tend to be periodic, beginning in the patient’s twenties; a later onset is more usually coupled with depression, treatment of which is discussed in Chap. 48. Most often, panic in younger persons is a component of a generalized anxiety disorder (see below), but it may stand alone as the only mental symptom or be an opening feature of schizophrenia.


Neurology_Adams

Neurology_Adams. Episodic or sustained anxiety without a disorder of mood (i.e., without depression) is classified as generalized anxiety disorder, as reviewed by Stein and Sareen, or formerly, anxiety neurosis. The more colorful term neurocirculatory asthenia (among many others) had been applied to the chronic form when accompanied by prominent fatigue and exercise intolerance, in which case it blends into the fatigue states discussed earlier. Some writings have emphasized that uncontrollable worry, as much or more than as nervousness, characterizes generalized anxiety disorder and that these patients describe a sense of helplessness in the face of their anxiety. This is contrasted to the experience of hopelessness that pervades depression.


Neurology_Adams

Neurology_Adams. The symptoms of anxiety may, however, be part of several other psychiatric disorders; it may be combined with other somatic symptoms in hysteria and is the most prominent feature of phobic disorder. Symptoms of persistent anxiety with insomnia, lassitude, and fatigue should always raise the suspicion of a depressive illness, especially when they begin in middle adult life or beyond. Also, unexplained anxiety or panic attacks may sometimes herald the onset of a schizophrenic illness. As with fatigue, the symptoms of both anxiety and depression are prominent features of the postconcussion syndrome, and of posttraumatic stress syndrome. These disorders highlight to us the difficulty in separating generalized anxiety disorder as a unique psychiatric entity. When visceral symptoms predominate or the psychic counterparts of fear and apprehension are absent, the presence of thyrotoxicosis, Cushing disease, pheochromocytoma, hypoglycemia, and menopausal symptoms should be considered.


Neurology_Adams

Neurology_Adams. This state has been alluded to previously in several contexts, but in the past decades it has come to have specific connotation and to stand as a separate disorder. The defining aspects are that an extremely stressful or traumatic event causes fear and helplessness, triggering a persistent psychologic state in which the patient reexperiences the event, avoids reminders of it, and is in a constant state of hyperarousal. Current diagnostic criteria require that this condition persist for over a month; if briefer, the condition is termed “acute stress disorder.”


Neurology_Adams

Neurology_Adams. Even proponents of posttraumatic stress disorder (PTSD) as a separate medical condition acknowledge that there is considerable overlap with anxious depression, the critical difference being the existence of a triggering traumatic event. They make the point that the original event may not be initially articulated by the patient but symptoms such as palpitations, dyspnea, dysphoria, and unexplained pains and other physical symptoms may be prominent, just as in depression. The biologic distinctions between anxious depression and PTSD include lower-than-normal cortisol levels, an attenuated increase of these levels in the immediate aftermath of the event, and an exaggerated suppression in response to dexamethasone. However, elevated circulating levels of norepinephrine and increased sensitivity of alpha2-adrenergic receptors that are found in the posttraumatic syndrome are shared with all other anxiety states (Southwick et al). Many of these studies have been poorly controlled.


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Neurology_Adams. It is apparent that there is a wide range of human vulnerability to persistent psychologic difficulties after traumatic events. In all probability, this parallels to some extent an endogenous susceptibility to PTSD. Examples of this are the elicitation of PTSD symptoms in susceptible persons by events not even witnessed personally, such as national disasters that are shared by large populations but produce symptoms in only a very few individuals.


Neurology_Adams

Neurology_Adams. The authors’ view is in agreement with the consensus that PTSD represents a special type of induced anxiety state with fairly stereotyped psychologic aspects, often with an accompanying depression and somatic symptoms. Separating it by highlighting the triggering event serves a useful nosologic purpose and draws attention to the need for acute treatment and subsequent support of individuals who have experienced a serious traumatic event such as rape or other violent attack and those returning from battle or after. An emerging notion is that sedatives or narcotics administered immediately after the inciting event may reduce the incidence and severity of PTSD, for example in battlefield conditions.


Neurology_Adams

Neurology_Adams. Selective serotonin reuptake inhibitors have been suggested for initial treatment but the other classes of antidepression drugs are also effective. Limiting anxiolytics such as benzodiazepines is recommended, but there are few data on which to make these judgments. A sympathetic physician is helpful in reassuring affected individuals and giving them perspectives to cope with the trauma and various cognitive-behavioral therapies and imagery have been useful but infrequently tested in a rigorous fashion. The review by Yehuda is informative on this subject and many of the comments above are taken from her summary.


Neurology_Adams

Neurology_Adams. The psychologic phenomenon of stress is closely allied to nervousness, fatigue, and anxiety and all of them are pervasive features of modern life. In general terms, stress has been defined as a feeling of self-doubt about being able to cope with some situation over a period of time. The term stress syndrome refers to perturbations of behavior and accompanying physiologic changes that are ascribable to environmental challenges of such intensity and duration as to overwhelm the individual’s adaptive capacity. The biologic effects of this phenomenon can be recognized in many species; chickens laying fewer eggs when moved to a new coop and cows giving less milk when put in a new barn, or monkeys going berserk when repeatedly frustrated by threats that they cannot control. Human beings forced to work under confined conditions and constant danger and cultural groups removed from their home and traditional way of life lose their coping skills and suffer anxiety and stress reactions.


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Neurology_Adams. Hans Selye, influenced by Pavlov’s concepts of stress, produced lesions in the visceral organs by exposing animals to life-threatening stressors combined with corticosteroids. Cardiac contraction-band necrosis and the shallow hemorrhagic gastrointestinal tract lesion (Cushing ulcer) are two examples of such catecholamine-mediated organ damage that is precipitated by acutely stressful circumstances. The dramatic syndrome of ballooning of the left ventricular apex, or takotsubo-like cardiomyopathy (so-named for the shape of the Japanese octopus trapping pot), is a manifestation of catecholamine excess caused by acute stress.


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Neurology_Adams. There is also equivocal epidemiologic evidence that chronic stress in individuals, captured in what has been termed the type A personality, raises the risk of cardiac disease, but the mechanism here, if it indeed exists, is likely to be through a physiologic intermediary such as systemic hypertension or perhaps inflammation that leads to atherosclerosis. Presumably, they have an increased output of “stress hormones” (cortisol and adrenaline).


Neurology_Adams

Neurology_Adams. Such psychologic disorders, bearing a direct relationship to environmental stressors, are among the most common occupational health problems. Stress syndromes are distinguished from anxiety disorders, in which the psychologic disturbance arises from within the individual and has no definite relationship to environmental stimuli. Whether certain individuals are by nature hyperresponsive to such stimuli is not known. The only therapeutic approach is to attempt to alter the patient’s perception of stress—for example, with psychotherapy and meditation exercises—and to remove him, if possible, from recognizable environmental stressors. (See “Editorial” in references.)


Neurology_Adams

Neurology_Adams. The phenomenon of irritability, or an irritable mood, must be familiar to almost everyone, exposed as we are to all of the noise, niggling inconveniences, and annoyances of daily life. It is, nevertheless, a difficult symptom to interpret in the context of psychopathology. Freud used the term Reisbarkeit in a restricted sense to denote an undue sensitivity to noise—and considered it a manifestation of anxiety, but obviously, this symptom has a much broader connotation and significance. For one thing, some people are by nature irritable throughout life. Also, irritability is an almost expected reaction in overworked, overwrought individuals, who become irritable by force of circumstances. An irritable mood or feeling may be present without observed manifestations (inward irritability), or there may be an overt loss of control of temper, with irascible verbal and behavioral outbursts, provoked by trivial but frustrating events.


Neurology_Adams

Neurology_Adams. Irritability in the foregoing circumstances can hardly be considered a departure from normal. However, when it becomes a recurrent event in a person of normally placid temperament, it assumes greater significance, for it may then signify the onset of a frontal lobe disorder including a variety of dementias, or of an ongoing anxiety state or depression. Irritability is also a common symptom of obsessive–compulsive disorders. Here the irritability tends to be directed inward, indicating perhaps a sense of frustration with personal disability (Snaith and Taylor). Depressed patients are frequently irritable; as a corollary, this symptom should always be sought in patients suspected of being depressed. The days preceding menses and the mother’s common postnatal mood disorder are characterized by high levels of outwardly directed irritability. Short-temperedness and irritability are also common features of the manic state. The most extreme degrees of irritability, exemplified by repeated


Neurology_Adams

Neurology_Adams. by high levels of outwardly directed irritability. Short-temperedness and irritability are also common features of the manic state. The most extreme degrees of irritability, exemplified by repeated quarrelsome and assaultive behavior (irritable aggression), are rarely observed in anxiety disorders and endogenous depression but are usually the mark of sociopathy and conventional brain disease (in the past, general paresis). Such irritable aggression is also observed in some patients with Alzheimer disease and other types of dementia, particularly of the frontotemporal type, and following traumatic contusions or encephalitis of the temporal and frontal lobes.


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Neurology_Adams. Cause, Mechanism, and Biologic Significance of Nervousness and Anxiety


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Neurology_Adams. These have been the subjects of much biologic and psychologic speculation, and completely satisfactory explanations are not available. As noted above, some individuals go through life in a chronic state of low-grade anxiety, the impetus for which may or may not be apparent. Spontaneous episodes of anxiety demand another explanation. Some psychologists regard anxiety as anticipatory behavior, that is, a state of uneasiness about something that may happen in the future. William McDougall spoke of it as “an emotional state arising when a continuing strong desire seems likely to miss its goal.” The primary emotion, somewhat muted perhaps, may be one of fear, and its arousal under conditions that are not overtly threatening may be explained as a conditioned response to some recondite component of a formerly threatening stimulus. The James-Lange theory of emotion, which is dated but should not be dismissed, suggests that the dominant feature of the experience of anxiety is simply the


Neurology_Adams

Neurology_Adams. of a formerly threatening stimulus. The James-Lange theory of emotion, which is dated but should not be dismissed, suggests that the dominant feature of the experience of anxiety is simply the physical experience of the associated autonomic discharge.


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Neurology_Adams. Infusions of lactic acid can make the symptoms of anxiety worse and, in susceptible individuals, may elicit a panic attack. The patient seems not to tolerate the work or exercise needed to build up stamina. The urinary excretion of epinephrine was found to be elevated in some patients with panic disorder; in others, there is an increased urinary excretion of norepinephrine and its metabolites. During periods of intense anxiety, aldosterone excretion is increased to 2 or 3 times normal.


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Neurology_Adams. There is evidence that corticosteroids and corticotropin- releasing hormone (CRH) have a role in the genesis of anxiety. A systemic release of corticosteroid accompanies all states of stress, and the administration of corticosteroids may give rise to anxiety and panic in some patients and to depression in others, suggesting a linkage between steroid stimulation of the limbic system activities that generate these states. In animal models, stress elicited by predators or electric shock as well as by withdrawal of alcohol and other drugs precipitates activity in CRH pathways (amygdala to hypothalamus, raphe nuclei, nucleus ceruleus, and other regions of the brainstem); blocking such activity by drugs or by destruction of the amygdala eliminates anxiety and fear-like behavior. Admittedly, the concepts of fear, stress, and anxiety are used interchangeably in these models, but repeated stimuli that produce fear and stress may eventually induce a state akin to anxiety, and the amygdala


Neurology_Adams

Neurology_Adams. the concepts of fear, stress, and anxiety are used interchangeably in these models, but repeated stimuli that produce fear and stress may eventually induce a state akin to anxiety, and the amygdala appears to be involved in the perpetuation of this anxiety state. The meaning of these effects, that is, whether they are primary or secondary, is not certain, but it is evident that prolonged and diffuse anxiety is associated with certain biochemical abnormalities of the blood and probably of the brain.


Neurology_Adams

Neurology_Adams. In addition to the role of the amygdala, animal studies have related acute anxiety to a disturbance of function of the locus ceruleus and the septal and hippocampal areas, the principal norepinephrine-containing nuclei. The locus ceruleus is involved in rapid eye movement (REM) sleep and drugs such as the tricyclic antidepressants and monoamine oxidase inhibitors, which suppress REM sleep, also decrease anxiety. Certain of the serotonin receptors in the brain, different from those implicated in depression, have been related to anxiety. Other parts of the brain must also be involved; bifrontal orbital leukotomy diminishes anxiety, possibly by interrupting the medial forebrain connections with the limbic parts of the brain. Positron emission tomography (PET) studies in subjects who anticipate an electric shock show enhanced activity in the temporal lobes and insula, implicating these regions in the experience of acute anxiety (see also “Physiology of the Limbic System” in Chap. 25).


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Neurology_Adams. an electric shock show enhanced activity in the temporal lobes and insula, implicating these regions in the experience of acute anxiety (see also “Physiology of the Limbic System” in Chap. 25). Other credible studies have demonstrated a role for the anterior cingulate gyrus in eliciting many of the autonomic features (particularly increased heart rate) of excessive arousal and anxiety.


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Neurology_Adams. Several other alterations in neurotransmitter function have been implicated in the anxious state. The finding that a small proportion of the inherited personality trait of anxiety can be accounted for by one polymorphism of the serotonin transporter gene is provocative (Lesch et al) but requires confirmation. DEPRESSIVE REACTIONS (SEE ALSO CHAP. 48)