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Neurology_Adams. Woods BT, Schaumburg HH: Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia. A unique and partially treatable clinico-pathological entity. J Neurol Sci 17:149, 1972. Wooten GF: Agonists vs levodopa in PD. Neurology 60:360, 2003. Worster-Drought C, Greenfield JG, McMenemey WH: A form of familial progressive dementia with spastic paralysis. Brain 67:38, 1944. Wu CK, Hohler AD. Management of orthostatic hypotension in patients with Parkinson’s disease. Pract Neurol 15:100, 2015. Young AB, Shoulson I, Penney JB, et al: Huntington’s disease in Venezuela: Neurologic features and functional decline. Neurology 36:244, 1986. Younger DS, Rowland LP, Latov N, et al: Motor neuron disease and amyotrophic lateral sclerosis: Relation of high CSF protein content to paraproteinemia and clinical syndromes. Neurology 40:595, 1990. Yuasa T, Ohama E, Harayama H, et al: Joseph’s disease: Clinical and pathological studies in a Japanese family. Ann Neurol 19:152, 1986.


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Neurology_Adams. Yuasa T, Ohama E, Harayama H, et al: Joseph’s disease: Clinical and pathological studies in a Japanese family. Ann Neurol 19:152, 1986. Zeman W: Pathology of the torsion dystonias (dystonia musculorum deformans). Neurology 20(No 11, Pt 2):79, 1970. Zwergal A, la Fougere C, Lorenzl S, et al: Postural imbalance and falls in PSP correlate with functional pathology of the thalamus. Neurology 77:101, 2011. Figure 38-1. Photomicrograph of Alzheimer amyloid plaques and neurofibrillary tangles. Bielschowsky silver stain. NH2COOH*****Mutations in APP, or ˜ secretase,and the Apo E4 allele enhance toxicity. ß secretaseAPP˜ secretaseAPPsßß stubApo EAß42FibrillogenesisAmyloidneurotoxicityDownsyndromeß ˛ß˜


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Neurology_Adams. Figure 38-2. Diagram of proteolysis of amyloid precursor protein (APP). When APP is cleaved sequentially by β secretase and then secretase, the resulting amyloid protein can be 40 (Aβ40) or 42 (Aβ42) amino acids in length. The latter favors the formation of aggregated fibrillary amyloid protein (fibrillogenesis) rather than normal APP degradation. The fibrillary form of amyloid is neurotoxic, a mechanism favored as the cause of cell damage in Alzheimer disease. Formation of Aβ42 is promoted by mutations, either in the APP gene itself or in the presenilins. In Down syndrome, excess production of APP and its product Aβ42 is caused by triplication of the long arm of chromosome 21, the location of the APP gene. The Apo E4 allele is associated with inadequate clearance of Aβ42 and is another mechanism that promotes fibrillogenesis. (Modified by permission from Sisodia SS, St. George–Hyslop PH: γ-Secretase, notch, Aβ and Alzheimer disease: Where do the presenilins fit in? Nat Rev Neurosci


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Neurology_Adams. mechanism that promotes fibrillogenesis. (Modified by permission from Sisodia SS, St. George–Hyslop PH: γ-Secretase, notch, Aβ and Alzheimer disease: Where do the presenilins fit in? Nat Rev Neurosci 3:281–290, 2002.)


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Neurology_Adams. Figure 38-3. Top: Coronal T1-weighted MRI of a 74-year-old man with moderate Alzheimer-type dementia. Diffuse cerebral and hippocampal atrophy with ex vacuo ventricular and cortical sulcal dilation is noted. Bottom: Coronal T1-weighted MRI of a 70-year-old woman with behavioral variant frontotemporal lobar dementia. Atrophy of the right greater than left temporal lobes is out of proportion to atrophy of the frontal and parietal lobes. Figure 38-4. Axial CT from a 54-year-old mildly demented woman with a 10-year history of Huntington chorea. The bulge in the inferolateral border of the lateral ventricle, normally created by the head of the caudate nucleus, is absent. There is also diffuse enlargement of the lateral ventricles.


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Neurology_Adams. Figure 38-5. Photomicrograph of a round Lewy body inclusion in the cytoplasm of a nigral neuron. (Hematoxylin and eosin [H&E] staining.) (From Frosch MP, et al: The central nervous system. In Robbins SL, et al (eds): Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia, Saunders/Elsevier, 2010.)


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Neurology_Adams. Figure 38-6. Schematic diagram of proposed mechanisms of α-synuclein toxicity in Parkinson disease. In this model, α-synuclein levels are elevated by (a) duplication of one copy of the α-synuclein gene; (b) point mutations in the α-synuclein gene that generate excessive accumulations of synuclein; or (c) mutations in parkin and UCH-L1 genes that reduce normal removal of synuclein by the proteosomes. The excess of synuclein polymerizes to form protofibrils, a process that is enhanced by defects in heat shock proteins (Hsps) or by the action of dopamine, which binds to synuclein. In turn, this leads to formation of Lewy bodies. This model attributes the neurotoxicity to either the protofibrils or the Lewy bodies. (Adapted by permission from Eriksen JL, Dawson TM, Dickson DW, Petrucelli L: Caught in the act: α-Synuclein is the culprit in Parkinson’s disease. Neuron 40:453–456, 2003.)


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Neurology_Adams. Figure 38-7. Progressive supranuclear palsy. A. T2-weighted axial MRI showing the atrophic dorsal midbrain that gives rise to the “mouse ears” (also “Mickey mouse”) appearance. B. Mid-sagittal image showing atrophy of the dorsal midbrain, giving the appearance of a hummingbird. Figure 38-8. Familial cortical cerebellar atrophy. T1-weighted MRI in the sagittal plane showing marked atrophy of vermis and enlargement of fourth ventricle. The brainstem is only mildly atrophic and the posterior fossa is normal is size. Compare with Fig. 38-9 in which the cerebellum and pons are atrophic. Figure 38-9. MSA-C, formerly called olivopontocerebellar atrophy. MRI in the sagittal plane demonstrating both vermian atrophy (black arrow) and smallness of the pons (white arrow). (Reproduced by permission from Bisese JH: Cranial MRI. New York, McGraw-Hill, 1991.)


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Neurology_Adams. Figure 38-10. Axial T2-weighted MRI showing abnormal hyperintensity reflecting wallerian change in the corticospinal tracts at the level of the internal capsule (top, arrow) and the pons (bottom) in a patient with ALS. Chapter 38 Degenerative Diseases of the Nervous System The Acquired Metabolic Disorders of the Nervous System


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Neurology_Adams. Chapter 38 Degenerative Diseases of the Nervous System The Acquired Metabolic Disorders of the Nervous System An important segment of neurologic medicine, and one that is seen with great frequency in general hospitals, are disorders in which a global disturbance of cerebral function (encephalopathy) results from failure of some other organ system—heart and circulation, lungs and respiration, kidneys, liver, pancreas, and the endocrine glands. Unlike the diseases considered in Chap. 36, in which a genetic abnormality affects the metabolic functions of many organs and tissues including the brain, the cerebral disorders discussed in this chapter are strictly secondary to derangements of the visceral organs themselves. They stand at the interface of internal medicine and neurology.


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Neurology_Adams. Relationships of this type, between an acquired disease of some thoracic, abdominal, or endocrine organ and the brain, have rather interesting implications. In the first place, recognition of the neurologic syndrome may be a guide to the diagnosis of the systemic disease; indeed, the neurologic symptoms may be more informative and significant than the symptoms referable to the organ primarily involved. Moreover, these encephalopathies are often reversible if the systemic dysfunction is brought under control. Neurologists must therefore have an understanding of the underlying medical disorder, for this may provide the means of controlling the neurologic part of the disease. In other words, the therapy for what appears to be a nervous system disease lies squarely in the field of internal medicine—a clear reason why every neurologist should be well trained in internal medicine. Of more theoretical importance, the investigation of the acquired metabolic diseases provides new insights into


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Neurology_Adams. clear reason why every neurologist should be well trained in internal medicine. Of more theoretical importance, the investigation of the acquired metabolic diseases provides new insights into the chemistry and pathology of the brain. Each visceral disease affects the brain in a somewhat different way and, because the pathogenic mechanism is not completely understood in any of them, the study of these metabolic diseases promises rich rewards to the scientist.


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Neurology_Adams. Table 39-1 lists the main acquired metabolic diseases of the nervous system according to their most common modes of clinical expression. Not included are the diseases caused by nutritional deficiencies and those caused by exogenous drugs and toxins, which can be considered metabolic in the broad sense; these are discussed in Chaps. 40 and 41, respectively. DISEASES PRESENTING AS CONFUSION, STUPOR, OR COMA (METABOLIC ENCEPHALOPATHY) The syndrome of impaired consciousness, its general features, the terms used to describe it, and the mechanisms involved are discussed in Chap. 16. There it was pointed out that metabolic disturbances are frequent causes of impaired consciousness and that their presence must always be considered when there are no focal signs of cerebral disease and both the imaging studies and the cerebrospinal fluid (CSF) are normal.


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Neurology_Adams. Intoxication with alcohol and other drugs figures prominently in the differential diagnosis. The main feature of the reversible metabolic encephalopathies is confusion, typified by disorientation and inattentiveness and accompanied in certain special instances by asterixis, tremor, and myoclonus, usually without signs of focal cerebral disease. This state may progress in stages to one of stupor and coma. Slowing of the background rhythms in the electroencephalogram (EEG) reflects the severity of the metabolic disturbance. With few exceptions, usually pertaining to cerebral edema and certain cases of hepatic or hypoxic-ischemic encephalopathy, imaging studies are normal. Seizures may or may not occur, most being associated with particular underlying causes of encephalopathy such as hyponatremia and hyperosmolarity.


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Neurology_Adams. Laboratory examinations are highly informative in the investigation of the acquired metabolic diseases. In patients with symptoms suggestive of a metabolic encephalopathy the following determinations are usually made: serum Na, K, Cl, Ca, Mg, glucose, HCO3, renal function tests (blood urea nitrogen [BUN] and creatinine), liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, NH3), thyroid function tests (T4 and thyroid-stimulating hormone [TSH]), and osmolality and, in certain cases, oxygen saturation and blood gas determinations. These are almost always supplemented by toxicology tests and measurement of the serum concentrations of relevant medications as discussed in the next chapter. Serum osmolality can be measured directly or calculated from the values of Na, glucose, and BUN (in mg/dL), using the following formula:


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Neurology_Adams. Normal serum osmolality is 270 to 290 mOsm/L. When there is a discrepancy of greater than 10 mOsm/L between the calculated and the directly measured values (osmolal, or osmolar gap), it can be assumed that additional circulating ions are present. Most often they are derived from an exogenous toxin or drug such as mannitol, but renal failure, ketonemia, or an increase of serum lactate may result in the accumulation of small molecules that contribute to the measured serum osmolality. A point to be remembered is that the brain may be damaged, even to an irreparable degree, by a disturbance of blood chemistry (e.g., hypoglycemia, hypoxia) that has vanished by the time the patient is examined.


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Neurology_Adams. Here the basic disorder is a lack of oxygen and of blood flow to the brain, the result of failure of the heart and circulation or of the lungs and respiration. Often, both are responsible and one cannot say which predominates; hence the dually ambiguous allusions in medical records to “hypoxic-ischemic” encephalopathy. This combined encephalopathy in various forms and degrees of severity is one of the most frequent and disastrous cerebral disorders encountered in every general hospital.


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Neurology_Adams. Reduced to the simplest formulation, a deficient supply of oxygen to the brain is either the result of a failure of cerebral perfusion (ischemia) or of a reduced amount of circulating arterial oxygen, of diminished oxygen saturation, or of insufficiency of hemoglobin (hypoxia). Although they are often combined, the neurologic effects of ischemia and hypoxia are subtly different. The medical conditions that most often lead to it are as follows: 1. A global reduction in cerebral blood flow (myocardial infarction, ventricular arrhythmia, aortic dissection, external or internal blood loss, and septic or traumatic shock) 2. Hypoxia from suffocation (drowning, strangulation, or aspiration of vomitus, food, or blood; from compression of the trachea by a mass or hemorrhage; tracheal obstruction by a foreign body, general anesthesia accident, narcotic overdose, extreme asthma) 3. As a subset of the above, diseases that paralyze the respiratory muscles (Guillain-Barré syndrome, amyotrophic


Neurology_Adams

Neurology_Adams. by a foreign body, general anesthesia accident, narcotic overdose, extreme asthma) 3. As a subset of the above, diseases that paralyze the respiratory muscles (Guillain-Barré syndrome, amyotrophic lateral sclerosis, myasthenia, and, in the past, poliomyelitis) or damages the medulla and leads to failure of breathing 4. The special case of carbon monoxide (CO) poisoning (nonischemic hypoxia)


Neurology_Adams

Neurology_Adams. The product of blood oxygen content and cardiac output is the ultimate determinant of the adequacy of oxygen supply to the organs. When blood flow is stable, the most important element in the delivery of oxygen is the oxygen content of the blood. This is the product of hemoglobin concentration and the percentage of oxygen saturation of the hemoglobin molecule. At normal temperature and pH, hemoglobin is 90 percent saturated at an oxygen partial pressure of 60 mm Hg and still 75 percent saturated at 40 mm Hg; that is, as is well known, the oxygen saturation curve is not linear. Physiology of Hypoxic and Ischemic Damage


Neurology_Adams

Neurology_Adams. A number of physiologic mechanisms of a homeostatic nature protect the brain under conditions of both ischemia and hypoxia. Through a mechanism termed autoregulation, there is a compensatory dilatation of resistance vessels in response to a reduction in cerebral perfusion, which maintains blood flow at a constant rate, as noted in Chap. 33. When the cerebral blood pressure falls below 60 to 70 mm Hg, an additional compensation in the form of increased oxygen extraction allows normal energy metabolism to continue. In total cerebral ischemia, the tissue is depleted of its sources of energy in about 5 min, although longer periods are tolerated under conditions of hypothermia. Also, energy failure because of hypoxia is counteracted by an autoregulatory increase in cerebral blood flow; at a Po2 of 25 mm Hg, the increase in blood flow is approximately 400 percent. A similar increase in flow occurs with a decrease in hemoglobin to 20 percent of normal.


Neurology_Adams

Neurology_Adams. In most clinical situations in which the brain is deprived of adequate oxygen, as already commented, there is a combination of ischemia and hypoxia, with one or the other predominating. The pathologic effects of ischemic brain injury from systemic hypotension differ from those caused by pure anoxia. Under conditions of transient ischemia, one pattern of damage takes the form of incomplete infarctions in the border zones between major cerebral arteries (Chap. 33). With predominant anoxia, neurons in portions of the hippocampus and the deep folia of the cerebellum are particularly vulnerable. More severe degrees of either ischemia or hypoxia, or the combination, lead to selective damage to certain layers of cortical neurons, and if more profound, to generalized damage of all the cerebral cortex, deep nuclei, and cerebellum. The nuclear structures of the brainstem and spinal cord are relatively resistant to anoxia and hypotension and stop functioning only after the cortex has been badly


Neurology_Adams

Neurology_Adams. deep nuclei, and cerebellum. The nuclear structures of the brainstem and spinal cord are relatively resistant to anoxia and hypotension and stop functioning only after the cortex has been badly damaged.


Neurology_Adams

Neurology_Adams. The cellular pathophysiology of neuronal damage under conditions of ischemia is discussed in Chap. 33. One mechanism of injury is an arrest of the aerobic metabolic processes necessary to sustain the Krebs (tricarboxylic acid) cycle and the electron transport system. Neurons, if completely deprived of their source of energy, are unable to maintain their integrity and undergo necrosis. However, neuronal cell death occurs through more than one mechanism. The most acute forms of cell death are characterized by massive swelling and necrosis of neuronal and nonneuronal cells (cytotoxic edema). Short of immediate ischemic necrosis, a series of internally programmed cellular events may also propel the cell toward death in a delayed fashion, a process for which the term apoptosis has been borrowed from embryology. There is experimental evidence that certain excitatory neurotransmitters, particularly glutamate, contribute to the rapid destruction of neurons under conditions of anoxia and


Neurology_Adams

Neurology_Adams. from embryology. There is experimental evidence that certain excitatory neurotransmitters, particularly glutamate, contribute to the rapid destruction of neurons under conditions of anoxia and ischemia (Choi and Rothman); the pertinence of these effects to clinical situations is uncertain. Ultimately, this process may be affected by massive calcium influx through a number of different membrane channels, which activates various kinases that participate in the process of gradual cellular destruction. Free radical generation appears to play a role in membrane dissolution as a result of these processes. As shown in experimental models, one of the reasons for the irreversibility of ischemic lesions may be swelling of the endothelium and blockage of circulation into the ischemic cerebral tissues, the “no-reflow” phenomenon described by Ames and colleagues. There is also a poorly understood phenomenon of delayed neurologic deterioration after anoxia; this may be a result of the blockage or


Neurology_Adams

Neurology_Adams. the “no-reflow” phenomenon described by Ames and colleagues. There is also a poorly understood phenomenon of delayed neurologic deterioration after anoxia; this may be a result of the blockage or exhaustion of some enzymatic process during the period when brain metabolism is restored.


Neurology_Adams

Neurology_Adams. Clinical Features of Hypoxic Encephalopathy Mild degrees of hypoxia without loss of consciousness induce only inattentiveness, poor judgment, and incoordination; in our experience, there have been no or minimal lasting clinical effects in such cases, although Hornbein and colleagues found a slight decline in visual and verbal long-term memory and mild aphasic errors in Himalayan mountaineers who had earlier ascended to altitudes of 18,000 to 29,000 ft. These observations make the point that profound anoxia may be well tolerated if arrived at gradually. For example, we have seen several patients with advanced pulmonary disease who were fully awake when their arterial oxygen pressure was in the range of 30 mm Hg. This level, if it occurs abruptly, causes coma. An important derivative observation is that degrees of hypoxia that at no time abolish consciousness rarely, if ever, cause permanent damage to the nervous system.


Neurology_Adams

Neurology_Adams. In the circumstances of severe global ischemia with prolonged loss of consciousness, the clinical effects can be quite variable. Following cardiac arrest, for example, consciousness is lost within seconds but recovery can be complete if breathing, oxygenation, and cardiac action are restored within 3 to 5 min. Beyond 5 min there is usually permanent injury. Clinically, however, it is often difficult to judge the precise degree and duration of ischemia, because slight heart action or an imperceptible blood pressure may have served to maintain the circulation to some extent. Hence some individuals have made an excellent recovery after cerebral ischemia that apparently lasted 8 to 10 min or longer. Subnormal body temperatures, as might occur when the body is immersed in ice-cold water, greatly prolong the tolerable period of hypoxia. This has led to the successful application of moderate cooling after cardiac arrest as a technique to limit cerebral damage (see further on in Treatment of


Neurology_Adams

Neurology_Adams. prolong the tolerable period of hypoxia. This has led to the successful application of moderate cooling after cardiac arrest as a technique to limit cerebral damage (see further on in Treatment of Hypoxic-Ischemic Encephalopathy section).


Neurology_Adams

Neurology_Adams. Generally speaking, anoxic patients who demonstrate intact brainstem function as indicated by normal pupillary light and ciliospinal responses, reflexive eye movements induced by passive head turning (doll’s eye movements), and other vestibulo-ocular reflexes have a more favorable outlook for recovery of consciousness and perhaps of all mental faculties. Conversely, the absence of these brainstem reflexes even after circulation and oxygenation have been restored, particularly pupils that fail to react to light, implies a grave outlook as elaborated further on. If the damage is almost total, coma persists, decerebrate postures may be present spontaneously or in response to painful stimuli, and bilateral Babinski signs can be evoked. In the first 24 to 48 h, death may terminate this state in a setting of rising temperature, deepening coma, and circulatory collapse, or the syndrome of brain death intervenes, as discussed below.


Neurology_Adams

Neurology_Adams. Most patients who have suffered severe but lesser degrees of hypoxia will have stabilized their breathing and cardiac activity by the time they are first examined; yet they are comatose, with the eyes slightly divergent and motionless but with reactive pupils, the limbs inert and flaccid or intensely rigid, and the tendon reflexes diminished. Within a few minutes after cardiac action and breathing have been restored, generalized convulsions and isolated or grouped myoclonic twitches may occur. Either of these phenomena are poor prognostic signs. With severe degrees of injury, the cerebral and cerebellar cortices and parts of the thalami are partly or completely destroyed but the brainstem-spinal structures survive. Tragically, the individual may survive for an indefinite period in a state that is variously referred to as cortical death, irreversible coma, or persistent vegetative state (see discussion of these subjects in Chap. 16). Some patients remain mute, unresponsive, and unaware


Neurology_Adams

Neurology_Adams. that is variously referred to as cortical death, irreversible coma, or persistent vegetative state (see discussion of these subjects in Chap. 16). Some patients remain mute, unresponsive, and unaware of their environment for weeks, months, or years. Long survival is usually attended by some degree of improvement but the patient appears to know nothing of his present situation and to have lost all past memories, cognitive function, and capacity for meaningful social interaction and independent existence (a minimally conscious state, actually a severe dementia; see Chap. 16). One has only to observe such patients and their families to appreciate the gravity of the problem, the family’s anguish, and the tremendous expense of medical care. The only person who does not appear to suffer is the patient.


Neurology_Adams

Neurology_Adams. With lesser degrees of anoxic-ischemic injury, the patient improves after a period of coma lasting hours or less. Some of these patients quickly pass through this acute post-hypoxic phase and proceed to make a full recovery; others are left with varying degrees of permanent disability.


Neurology_Adams

Neurology_Adams. The findings on imaging studies vary. The most common early change in cases of severe injury is a loss of the distinction between the cerebral gray and white matter (Fig. 39-1); patients with this finding are invariably comatose and few awaken with a good neurologic outcome. With less severe and predominantly hypotensive-ischemic events such as cardiac arrest, arterial borderzone (watershed) infarctions become evident in the border zones between the anterior, middle, and posterior cerebral arteries (Fig. 39-2). The clinical syndromes associated with borderzone infarction are discussed below. Yet another pattern of brain destruction, seen at times also in CO poisoning, consists of striatal damage that is evident more by imaging than by clinical features (Fig. 39-3). Brain Death From Hypoxia-Ischemia (See Chap. 16 for a Full Discussion)


Neurology_Adams

Neurology_Adams. Brain Death From Hypoxia-Ischemia (See Chap. 16 for a Full Discussion) This represents the most severe degree of hypoxia, usually caused by circulatory arrest; it is manifest by a state of complete unawareness and unresponsiveness with abolition of all brainstem reflexes. Natural respiration cannot be sustained; only cardiac action and blood pressure are maintained. No electrical activity is seen in the EEG (it is isoelectric). At autopsy one finds that most, if not all, the gray matter of cerebral, cerebellar, and brainstem structures—and in some instances, even the upper cervical spinal cord—has been severely damaged.


Neurology_Adams

Neurology_Adams. One must always exercise caution in concluding that a patient has this form of irreversible brain damage, because anesthesia, intoxication with certain drugs, and hypothermia may also cause deep coma and an isoelectric EEG but permit recovery. Therefore it is often advisable to repeat the clinical and laboratory tests after an interval of a day or so, during which time the results of toxic screening also become available. The authors’ experience corroborates the general notion that the vital functions of patients with the brain death syndrome usually cannot be sustained for more than several days without external intervention. In exceptional cases, however, the provision of adequate fluid, vasopressors, and respiratory support allows preservation of the body in a comatose state for longer periods. These issues are discussed extensively in Chap. 16.


Neurology_Adams

Neurology_Adams. The permanent neurologic sequelae or posthypoxic syndromes observed most frequently are as follows: 1. Persistent coma or stupor, described above 2. With lesser degrees of cerebral injury, dementia with or without extrapyramidal signs 3. Extrapyramidal (parkinsonian) syndrome with cognitive impairment (discussed in relation to CO poisoning) 4. Choreoathetosis 5. Cerebellar ataxia 6. Intention or action myoclonus (Lance-Adams syndrome) 7. An amnesic state


Neurology_Adams

Neurology_Adams. If hypoperfusion dominates, the patient may also display the manifestations of watershed infarctions that are situated between the end territories of the major cerebral vessels. The main syndromes that become evident soon after the patient awakens are as follows: 1. Visual agnosias including Balint syndrome and cortical blindness (Anton syndrome) (see Chap. 21), representing infarctions of the watershed between the middle and posterior cerebral arteries (see Fig. 39-2) 2. Proximal arm and shoulder weakness, sometimes accompanied by hip weakness (referred to as a “person [man]-in-the-barrel” syndrome), reflecting infarction in the territory between the middle and anterior cerebral arteries. These patients are able to walk, but their arms dangle and their hips may be weak.


Neurology_Adams

Neurology_Adams. The two watershed syndromes may rarely coexist. The interested reader may consult the appropriate chapter in the text on neurologic intensive care by Ropper and colleagues for further details. There are also watershed areas in the spinal cord (Chap. 42). Seizures may or may not be a problem, and when present are often resistant to treatment. Well-formed motor convulsions are infrequent. Myoclonus is more common and may be intermixed with fragmentary convulsions. Myoclonus is a grave sign in most cases but it generally recedes after several hours or a few days. These movements are also difficult to suppress, as noted further on.


Neurology_Adams

Neurology_Adams. This is a relatively uncommon and unexplained phenomenon. Initial improvement, which appears to be complete, is followed after a variable period of time (1 to 4 weeks in most instances) by a relapse, characterized by apathy, confusion, irritability, and occasionally agitation or mania. Most patients survive this second episode, but some are left with serious mental and motor disturbances (Choi; Plum et al). In still other cases, there appears to be progression of the initial neurologic syndrome with additional weakness, shuffling gait, diffuse rigidity and spasticity, sphincteric incontinence, coma, and death after 1 to 2 weeks. Exceptionally, there is yet another syndrome in which an episode of hypoxia is followed by slow deterioration, which progresses for weeks to months until the patient is mute, rigid, and helpless. In such cases, the basal ganglia are affected more than the cerebral cortex and white matter as in the case studied by our colleagues Dooling and Richardson.


Neurology_Adams

Neurology_Adams. the patient is mute, rigid, and helpless. In such cases, the basal ganglia are affected more than the cerebral cortex and white matter as in the case studied by our colleagues Dooling and Richardson. Instances have followed cardiac arrest, drowning, asphyxiation, and carbon monoxide poisoning.


Neurology_Adams

Neurology_Adams. The imaging features of the white matter disorder can be quite striking (Fig. 39-4). A mitochondrial disorder has been suggested, on uncertain grounds, as the underlying mechanism. Prognosis of Hypoxic-Ischemic Brain Injury (See Also “Prognosis in Coma” in Chap. 16)


Neurology_Adams

Neurology_Adams. Several models were developed before the era of current therapies to predict the outcome of hypoxic-ischemic coma. All of them incorporate simple clinical features involving loss of motor, verbal, and pupillary functions in various combinations. The most often cited study of the prognostic aspects of coma following cardiac arrest in the past had been by Levy and colleagues of 210 patients, which provided the following guidelines: 13 percent of patients attained a state of independent function within 1 year; at the time of the initial evaluation, approximately 25 percent of patients had absent pupillary light reflexes, none of whom regained independent function; by contrast, the presence on admission of reactive pupils, eye movements, and any motor response, a configuration displayed in approximately 10 percent, was associated with a better prognosis in almost 50 percent of cases. The absence of neurologic function in any of these spheres at 1 day after cardiac arrest, unsurprisingly,


Neurology_Adams

Neurology_Adams. 10 percent, was associated with a better prognosis in almost 50 percent of cases. The absence of neurologic function in any of these spheres at 1 day after cardiac arrest, unsurprisingly, was associated with an even poorer outcome. Similarly, Booth and colleagues analyzed previously published studies and determined that 5 clinical signs at 1 day after cardiac arrest predicted a poor neurologic outcome or death: (1) absent corneal responses, (2) absent pupillary reactivity, (3) no withdrawal to pain, and (4) the absence of any motor response. In the era of colling therapy, some of these clinical signs cannot be observed. In any case, concurrent intoxication must be excluded. The use of somatosensory evoked potentials in the prognostication of coma is discussed in Chaps. 2 and 16.


Neurology_Adams

Neurology_Adams. The question of what to do with patients in such states of protracted coma is a societal as much as a medical problem. The neurologist can reasonably be expected to state the level and degree of brain damage, its cause, and the prognosis based on their own and published experience. One prudently avoids heroic, lifesaving therapeutic measures once the nature of this state has been determined with certainty. However, some patients who show clinical and EEG cerebral reactivity to verbal commands will make a degree of recovery, most often to a disabled state. Treatment of Hypoxic-Ischemic Encephalopathy


Neurology_Adams

Neurology_Adams. Treatment of Hypoxic-Ischemic Encephalopathy Treatment is directed initially to the prevention of further hypoxic injury. A clear airway is secured, cardiopulmonary resuscitation is initiated, and every second counts in their prompt utilization. Supplemental oxygen may be of value during the first hours but is probably of little use after the blood becomes well oxygenated. Once cardiac and pulmonary function are restored, there is experimental and clinical evidence that reducing cerebral metabolic requirements by inducing hypothermia has a beneficial effect on outcome and may prevent the delayed worsening referred to above. The use of high-dose barbiturates has not met with the same success.


Neurology_Adams

Neurology_Adams. Much attention was drawn to the randomized trials conducted by Bernard and colleagues and by the Hypothermia After Cardiac Arrest Study Group, of mild hypothermia applied to unconscious patients immediately after cardiac arrest. They reduced the core temperature to 33çC (91çF) within 2 h of the arrest and sustained this level for 12 h in the first trial, and between 32çC and 34çC for 24 h in the second study. Both trials demonstrated improved survival and better cognitive outcome in survivors, compared to leaving the patient in a normothermic state; this led to the development of guidelines and a change in clinical practice in the United States and elsewhere after 2002. The outcomes were evaluated by coarse measures of neurologic function. Implementing and sustaining hypothermia is done either by external cooling, infusion of cooled normal saline, or intravenous cooling devices, and the iatrogenic problems of hypotension, bleeding, ventricular ectopy and infection have sometimes


Neurology_Adams

Neurology_Adams. either by external cooling, infusion of cooled normal saline, or intravenous cooling devices, and the iatrogenic problems of hypotension, bleeding, ventricular ectopy and infection have sometimes arisen, although this mild degree of temperature reduction is usually well tolerated. A third larger trial conducted by Nielsen and colleagues compared temperature maintenance after cardiac arrest at 33çC to maintenance of 36çC and found no difference in the rate of death or in neurological outcome. Whether these results should be interpreted as demonstrating that hypothermic treatment is ineffective or if, more likely, it is the avoidance of hyperthermia that creates an advantage is still under discussion.


Neurology_Adams

Neurology_Adams. A meta-analysis of trial data and observational studies by Schenone and colleagues concluded that therapeutic hypothermia after cardiac arrest was associated with benefit for survival and neurologic outcome (return to work or moderate disability), even when patients are included with asystole or pulseless electrical activity (PEA), prolonged duration of arrest, and those with persistent shock. Another systematic review by Arrich and colleagues also found that induced mild hypothermia improved neurological outcome after cardiac arrest, but found insufficient evidence to support therapeutic hypothermia in participants with in-hospital cardiac arrest, asystole, or noncardiac causes of arrest. It is difficult to gauge how many individuals were changed from the category of dying to one of vegetative or severely disabled state. Given a lack of other proven neuroprotective interventions, we generally favor initiation of induced hypothermia after cardiac arrest unless there are strong


Neurology_Adams

Neurology_Adams. of vegetative or severely disabled state. Given a lack of other proven neuroprotective interventions, we generally favor initiation of induced hypothermia after cardiac arrest unless there are strong clinical contraindications.


Neurology_Adams

Neurology_Adams. Vasodilator drugs, glutamate blockers, opiate antagonists, and calcium channel blockers have been of no proven benefit despite their theoretical appeal and some experimental successes. Corticosteroids ostensibly help to allay brain (possibly cellular) swelling, but, again, their therapeutic benefit has not been evident in clinical trials.


Neurology_Adams

Neurology_Adams. Seizures should be controlled by the methods indicated in Chap. 15. If convulsions are severe, continuous, and unresponsive to the usual medications, infusion of a drug such as midazolam or propofol, and eventually the suppression of convulsions with neuromuscular blocking agents may be required. Often the seizures cease after a few hours and are replaced by polymyoclonus. For the latter, clonazepam, 8 to 12 mg daily in divided doses may be useful but the commonly used antiepileptic drugs have little effect. A state of spontaneous and stimulus-sensitive myoclonus as well as persistent limb posturing usually presages a poor outcome. The striking disorder of delayed movement-induced myoclonus and ataxic tremor that appear after the patient awakens from an anoxic episode (Lance-Adams myoclonus) is a special issue, which is discussed in Chap. 4. Its treatment usually requires the use of multiple medications. Fever is treated with antipyretics or a cooling blanket combined with


Neurology_Adams

Neurology_Adams. myoclonus) is a special issue, which is discussed in Chap. 4. Its treatment usually requires the use of multiple medications. Fever is treated with antipyretics or a cooling blanket combined with neuromuscular paralyzing agents.


Neurology_Adams

Neurology_Adams. Strictly speaking, CO is an exogenous toxin, but it is considered here because it produces a characteristic cerebral injury and is frequently associated with delayed neurologic deterioration. The extreme affinity of CO for hemoglobin (more than 200 times that of oxygen) drastically reduces the oxygen content of blood and subjects the brain to prolonged hypoxia and acidosis. Cardiac toxicity and hypotension generally follow. Whether CO also has a direct toxic action on neuronal components is not settled. The effects on the brain for the most part simulate those caused by cardiac arrest. Neurologists are likely to encounter instances of CO poisoning in burn units and in patients who have attempted suicide or have been exposed accidentally to a faulty furnace or to car exhaust in a closed garage. A contemporary review of the subject has been given by Weaver.


Neurology_Adams

Neurology_Adams. Early symptoms include headache, nausea, dyspnea, confusion, dizziness, and clumsiness. These occur when the carboxyhemoglobin level reaches 20 to 30 percent of total hemoglobin. Exposure to relatively low levels of CO from faulty furnaces and gasoline engines should be suspected as the cause of recurrent headaches and confusion that clear upon hospitalization or other change of venue. A cherry-red color of the skin may appear, but is actually an infrequent finding; cyanosis is more common. At slightly higher levels of carboxyhemoglobin, blindness, visual field defects, and papilledema develop, and levels of 50 to 60 percent are associated with coma, decerebrate or decorticate posturing, seizures in a few patients, and generalized slowing of the EEG rhythms. The initial CT or MRI is normal or shows mild cerebral edema; later scans may show a characteristic lesion in the pallidum, as described below. Only if there has been associated hypotension does one see the same types of vascular


Neurology_Adams

Neurology_Adams. or shows mild cerebral edema; later scans may show a characteristic lesion in the pallidum, as described below. Only if there has been associated hypotension does one see the same types of vascular border-zone infarctions that appear after cardiac arrest.


Neurology_Adams

Neurology_Adams. Delayed neurologic deterioration 1 to 3 weeks (sometimes much longer) after CO exposure occurs more frequently than with other forms of cerebral hypoxia. In Choi’s survey, this feature was observed in 3 percent of 2,360 cases of CO poisoning and in 12 percent of those ill enough to be admitted to a hospital. Extrapyramidal features (parkinsonian gait and bradykinesia) predominated. Three-quarters of such patients were said to recover within a year. Discrete lesions centered in the globus pallidus bilaterally and sometimes the inner portion of the putamina are characteristic of CO poisoning that had produced coma (Fig. 39-5), but similar focal destruction may be seen after drowning, strangulation, and other forms of anoxia. The common feature among the delayed-relapse patients is a prolonged period of pure anoxia (before the occurrence of ischemia). Basal ganglia lesions may be quite prominent on CT even when delayed neurologic sequelae do not occur but they are invariably present


Neurology_Adams

Neurology_Adams. period of pure anoxia (before the occurrence of ischemia). Basal ganglia lesions may be quite prominent on CT even when delayed neurologic sequelae do not occur but they are invariably present between 1 and 4 weeks in patients who develop the delayed extrapyramidal syndrome. In less-severely affected patients we have seen such lesions resolve entirely on CT and MRI and there is no resultant movement disorder.


Neurology_Adams

Neurology_Adams. The initial treatment for carbon monoxide exposure is with inspired oxygen. Because the half-life of CO (normally 5 h) is greatly reduced by the administration of hyperbaric oxygen at 2 or 3 atmospheres, this additional treatment is recommended when the carboxyhemoglobin concentration is greater than 40 percent or in the presence of coma or seizures (Myers et al). According to a trial conducted by Weaver and colleagues, this treatment reduces the incidence of cognitive sequelae from 46 to 25 percent. They administered 3 hyperbaric sessions in the first 24 h after exposure to CO.


Neurology_Adams

Neurology_Adams. Acute mountain sickness is another special form of cerebral hypoxia. It occurs when a sea-level inhabitant abruptly ascends to a high altitude. Headache, anorexia, nausea and vomiting, weakness, and insomnia appear at altitudes above 8,000 ft; on reaching higher altitudes, there may be ataxia, tremor, drowsiness, mild confusion, and hallucinations. At 16,000 ft, according to Griggs and Sutton, 50 percent of individuals develop asymptomatic retinal hemorrhages, and it has been suggested that such hemorrhages also occur in the cerebral white matter. Extreme altitude sickness may result in fatal cerebral edema. The overexpression of vascular endothelial growth factor (VEGF), a protein originally noted for its effects on vascular permeability, has been implicated as the cause of cerebral edema in the experiments of Schoch and colleagues. With more prolonged exposure at these altitudes or with further ascent, affected individuals suffer mental impairment that may progress to coma.


Neurology_Adams

Neurology_Adams. edema in the experiments of Schoch and colleagues. With more prolonged exposure at these altitudes or with further ascent, affected individuals suffer mental impairment that may progress to coma. Hypoxemia at high altitudes is intensified during sleep, as ventilation normally diminishes and also by pulmonary edema, another manifestation of mountain sickness. Reference was made earlier to the observation of Hornbein and colleagues of a mild, but possibly lasting, memory impairment even in acclimated mountaineers who had been exposed to extremely high altitudes for several days. Hackett and Roach have reviewed the treatments for altitude illness.


Neurology_Adams

Neurology_Adams. Chronic mountain sickness, also called Monge disease (after the physician who described the condition in Andean Indians of Peru), is observed in long-term inhabitants of high-altitude mountainous regions. Pulmonary hypertension, cor pulmonale, and secondary polycythemia are the main features. There is usually hypercarbia as well, with the expected degree of mild mental dullness, slowness, fatigue, nocturnal headache, and, sometimes, papilledema (see in the following text). Thomas and colleagues have called attention to a syndrome of burning hands and feet in Peruvians at high altitude, apparently a maladaptive response to chronic hypoxia. Sedatives, alcohol, and a slightly elevated Pco2 in the blood all reduce tolerance to high altitude. Dexamethasone and acetazolamide prevent and counteract mountain sickness to some extent. The most effective preventive measure is acclimatization by a 2to 4-day stay at intermediate altitudes.


Neurology_Adams

Neurology_Adams. Chronic obstructive pulmonary disease such as emphysema, fibrosing lung disease, neuromuscular weakness, and, in some instances, inadequacy of the medullary respiratory centers each may lead to persistent respiratory acidosis, with elevated Pco2 and reduced arterial Po2. The complete clinical syndrome of chronic hypercapnia described by Austen et al comprises headache, papilledema, mental dullness, drowsiness, confusion, stupor and coma, and asterixis. More typically, only some of these features are found. Some patients have a fast-frequency tremor. The headache tends to be generalized, frontal, or occipital and can be quite intense, persistent, steady, and aching in type; nocturnal occurrence is a feature of some cases. The papilledema is bilateral but may be slightly greater in 1 eye than in the other, and hemorrhages may encircle the choked disc (a later finding). The tendon reflexes are lively and plantar reflexes may be extensor. Intermittent drowsiness, inattentiveness,


Neurology_Adams

Neurology_Adams. 1 eye than in the other, and hemorrhages may encircle the choked disc (a later finding). The tendon reflexes are lively and plantar reflexes may be extensor. Intermittent drowsiness, inattentiveness, reduction of psychomotor activity, inability to perceive all the items in a sequence of events, and forgetfulness constitute the more subtle manifestations of this syndrome and may prompt the family to seek medical help. Such symptoms may last only a few minutes or hours, and one cannot count on their presence at the time of a particular examination. In fully developed cases, the CSF is under increased pressure; Pco2 may exceed 75 mm Hg, and the O2 saturation of arterial blood ranges from 85 percent to as low as 40 percent. The EEG shows slow activity in the delta or theta range, which is sometimes bilaterally synchronous.


Neurology_Adams

Neurology_Adams. The mechanism of the cerebral disorder is from a direct CO2 narcosis, but the biochemical details are not known. Normally the CSF is slightly acidotic in comparison to the blood and the Pco2 of the CSF is about 10 mm Hg higher than that of the blood. With respiratory acidosis, the pH of the CSF falls (into the range of 7.15 to 7.25) and cerebral blood flow increases as a result of cerebral vasodilatation. However, the brain rapidly adapts to respiratory acidosis through the generation and secretion of bicarbonate by the choroid plexuses. Brain water content also increases, mainly in the white matter. In animal models of hypercarbia, blood and brain NH3 is elevated, which may explain the similarity of the syndrome to that of hyperammonemic liver failure (Herrera and Kazemi).


Neurology_Adams

Neurology_Adams. The most effective therapeutic measures are positive-pressure ventilation, using oxygen if there is also hypoxia. Oxygen supplementation is, of course, used cautiously in these patients in order to avoid suppressing respiratory drive; marginally compensated patients treated with excessive oxygen have lapsed into coma. Treatment of heart failure, phlebotomy to reduce the viscosity of the blood, and antibiotics to suppress pulmonary infection may be necessary. Often these measures result in a surprising degree of improvement, which may be maintained for months or years. If aminophylline is administered for the treatment of the underlying pulmonary airway disease, it may produce high blood levels and a tendency to produce seizures. Unlike pure hypoxic encephalopathy, prolonged coma because of hypercapnia is relatively rare and in our experience has not led to irreversible brain damage. Papilledema, myoclonus, and especially asterixis are important diagnostic features.


Neurology_Adams

Neurology_Adams. This condition is now relatively infrequent but is an important cause of confusion, convulsions, stupor, and coma; as such, it merits separate consideration as a metabolic disorder of the brain. The essential biochemical abnormality is a critical lowering of the blood glucose. At a level of about 30 mg/dL, the cerebral disorder takes the form of a confusional state and one or more seizures may occur; at a level of 10 mg/dL, there is coma that may result in irreparable injury to the brain if not corrected immediately by the administration of glucose. As with most other metabolic encephalopathies, the rate of decline of blood glucose is a factor in both the depression of consciousness and residual dementia.


Neurology_Adams

Neurology_Adams. The normal brain has a glucose reserve of 1 to 2 g (30 mmol/100 g of tissue), mostly in the form of glycogen. Because glucose is utilized by the brain at a rate of 60 to 80 mg/min, the glucose reserve may sustain cerebral activity for 30 min or less once blood glucose is no longer available. Glucose is transported from the blood to the brain by an active carrier system. Glucose entering the brain either undergoes glycolysis or is stored as glycogen. During normal oxygenation (aerobic metabolism), glucose is converted to pyruvate, which enters the Krebs cycle; with anaerobic metabolism, lactate is formed. The oxidation of 1 mole of glucose requires 6 mole of O2. Of the glucose taken up by the brain, 85 to 90 percent is oxidized; the remainder is used in the formation of proteins and other substances, notably neurotransmitters and particularly gamma-aminobutyric acid (GABA).


Neurology_Adams

Neurology_Adams. When blood glucose falls, the central nervous system (CNS) can utilize nonglucose substrates to a variable extent for its metabolic needs, especially keto acids and intermediates of glucose metabolism, such as lactate, pyruvate, fructose, and other hexoses. In the neonatal brain, which has a higher glycogen reserve, keto acids provide a considerable proportion of cerebral energy requirements; this also happens after prolonged starvation. However, in the face of severe and sustained hypoglycemia, these alternative substrates are inadequate to preserve the structural integrity of neurons, and eventually adenosine triphosphate (ATP) is depleted as well. If convulsions occur, they usually do so during a period of confusion; the convulsions have been attributed to an altered integrity of neuronal membranes and to elevated NH3 and depressed GABA and lactate levels (Wilkinson and Prockop).


Neurology_Adams

Neurology_Adams. The brain is the only organ besides the heart that suffers severe functional and structural impairment under conditions of severe hypoglycemia. Beyond what is described above, the pathophysiology of the cerebral disorder has not been fully elucidated. It is known that hypoglycemia reduces O2 uptake and increases cerebral blood flow. As with anoxia and ischemia, there is experimental evidence that the excitatory amino acid glutamate is involved in the process. The levels of several brain phospholipid fractions decrease when animals are given large doses of insulin. However, the suggestion that hypoglycemia results in a rapid depletion and inadequate production of high-energy phosphate compounds has not been corroborated; some other glucose-dependent biochemical processes must be implicated.


Neurology_Adams

Neurology_Adams. The most common causes of hypoglycemic encephalopathy are (1) accidental or deliberate overdose of insulin or an oral diabetic agent; (2) islet cell insulin-secreting tumor of the pancreas; (3) depletion of liver glycogen, which occasionally follows a prolonged alcoholic binge, starvation, or any form of severe liver failure; (4) glycogen storage disease of infancy; (5) an idiopathic hypoglycemia in the neonatal period and infancy; and (6) subacute and chronic hypoglycemia from islet cell hypertrophy and islet cell tumors of the pancreas, carcinoma of the stomach, fibrous mesothelioma, carcinoma of the cecum, and hepatoma. Purportedly, an insulin-like substance is elaborated by these nonpancreatic tumors. In the past, hypoglycemic encephalopathy was a not infrequent complication of “insulin shock” therapy for schizophrenia. In functional hyperinsulinism, as occurs in anorexia nervosa and dietary faddism, the hypoglycemia is rarely of sufficient severity or duration to damage the CNS.


Neurology_Adams

Neurology_Adams. The initial symptoms appear when the blood glucose has descended to about 30 mg/dL, nervousness, hunger, flushed facies, sweating, headache, palpitation, trembling, and anxiety. These gradually give way to confusion and drowsiness or occasionally, to excitement, overactivity, and bizarre or combative behavior. Many of the early symptoms relate to adrenal and sympathetic overactivity and some of the manifestations may be muted in diabetic patients with neuropathy. In the next stage, forced sucking, grasping, motor restlessness, muscular spasms, and decerebrate rigidity occur, in that sequence. Myoclonic twitching and convulsions develop in some patients. Rarely, there are focal cerebral deficits, the pathogenesis of which remains unexplained; according to Malouf and Brust, hemiplegia, corrected by intravenous glucose, was observed in 3 of 125 patients who presented with symptomatic hypoglycemia.


Neurology_Adams

Neurology_Adams. Blood glucose levels of approximately 10 mg/dL are associated with deep coma, dilatation of pupils, pale skin, shallow respiration, slow pulse and hypotonia, what had in the past been termed the “medullary phase” of hypoglycemia. If glucose is administered before this level has been attained, the patient can be restored to normal, retracing the aforementioned steps in reverse order. However, once this state is reached, and particularly if it persists for more than a few minutes, recovery is delayed for a period of days or weeks and may be incomplete as noted below. The EEG is altered as the blood glucose falls, but the correlations are imprecise. There is diffuse slowing in the theta or delta range. During recovery, sharp waves may appear and coincide in some cases with seizures.


Neurology_Adams

Neurology_Adams. The major clinical differences between hypoglycemic and hypoxic encephalopathy lie in the setting and the mode of evolution of the neurologic disorder. The effects of hypoglycemia usually unfold more slowly, over a period of 30 to 60 min, rather than in a few seconds or minutes. The recovery phase and sequelae of the two conditions are quite similar. A large dose of insulin, which produces intense hypoglycemia, even of relatively brief duration (30 to 60 min), is more dangerous than a series of less-severe hypoglycemic episodes from smaller doses of insulin, possibly because the former impairs or exhausts essential enzymes, a condition that cannot then be overcome by large quantities of intravenous glucose. Reflecting the benignity of repeated minor occurrences, the Diabetes Control and Complications Trial have demonstrated that recurrent hypoglycemic episodes in the course of treatment of diabetes over many years are very well tolerated and do not lead to cognitive decline.