Nutritional and Metabolic Insults 30
30.1 Starvation and Malnutrition 606 30.1.1 Protein Deficiency 606 30.1.2 Vitamin Deficiencies 606
30.1.3 Disturbances of Glucose Metabolism 607 30.1.3.1 Hypoglycemic Encephalopathy 607 30.1.3.2 Hyperglycemia 608
30.1.3.3 Diagnosis 608
30.2 Dissociation of Water and Electrolyte Balance 608
30.2.1 Dehydration 608 30.2.2 Hypernatremia 609
30.2.3 Hyponatremia and Water Intoxication 609 30.2.4 Hyponatremia
and Central Pontine Myelinolysis 610 30.3 Hepatic Encephalopathy 611 30.3.1 Fulminant Hepatic Failure 611 30.3.2 Chronic Liver Disease
and Portal-Systemic Bypass 611 30.3.3 Familial Hepatolenticular Degeneration
(Wilson’s Disease) 612 30.3.4 Reye’s Syndrome 612
30.4 Uremic Encephalopathy 612 30.4.1 Dialysis Encephalopathy 613
Bibliography 614
References 614
Nutritional and metabolic intoxicants inflict special types of exogenous and endogenous insults on the nervous system. The majority of these intoxicants are “endogenous” neurotoxins. The insults may also result from deficiencies in energy, vitamins, water, and electrolytes secondary to functional de- compensation of organs such as liver and kidney.
The final diagnosis of almost all of these toxins and deficiencies cannot be made by the neuropa- thologist, but requires the expertise of the clinician (medical history) and pathologist (autopsy) aided by clinical−biochemical or molecular findings. At best, neuropathological examination can confirm the di-
agnosis and specify the type of insult of the nervous system. Such an examination can also document the neurological and/or psychopathological deficits that were present during life.
Kunze (2002) recently provided the following definition of metabolic encephalopathies: “Encepha- lopathies are diffuse multifocal cerebral states that can be caused by any of a large number of organ dysfunctions and factors. They represent functional brain disturbances that initially are not associated with morphological correlates. Primary encepha- lopathies can be attributed to a variety of geneti- cally defined disturbances of carbohydrate, amino acid, and lipid metabolism. Secondary or metabolic encephalopathies are induced by systemic diseases, hypoxic−ischemic states, organ dysfunction of the liver, kidney, and lung, as well as by a variety of toxic agents. Although encephalopathy patients do not al- ways experience neuropathological changes, patients with vascular and specific hepatic encephalopathies tissue often exhibit cerebral ischemia, edema, and tissue necrosis. At the cellular level astrocytes may undergo morphological changes and resemble Al- zheimer type II cells.”
Morris and Ferrendelli (1990) have published a thorough survey of metabolic encephalopathies and their causes. The basic pathophysiology of encepha- lopathy is still not known. A probable cause is a dis- turbance of the blood−brain barrier, but this may be only one of a number of explanations.
The clinical features of encephalopathies vary in both quantity and quality. Predominant among the global symptoms are slight cognitive disturbances and confusion, especially in the early stages. During later phases of disease, symptoms can include severe confusional states, altered consciousness, autonomic dysfunctions, and psychomotor hyperactivity. Severe encephalopathy can feature global brain stem signs with pathological reflexes, abnormalities of muscle tone, oral and facial automatisms, tremor, changes in spontaneous movements, and multifocal myoclonus.
Among the focal cerebral symptoms are the various
neurological signs of the hemispheres and/or brain
stem. They generally do not predominate but are
combined with global signs.
Our remarks in the following will be limited to the principal types of encephalopathy. Moreover, some of the diseases discussed here are examined in their relation to children in Part V (pp. 407 ff).
30.1
Starvation and Malnutrition
30.1.1
Protein Deficiency
An active adult requires 1,500 to 2,000 calories per day to maintain body mass. A 40% loss of original body mass can be fatal; the outcome depends in large part on the speed of loss. If sufficient fluids are available, food deprivation can lead to death with- in 50−60 days. Water deprivation is fatal in about 10 days, even fewer if there are high ambient tem- peratures.
Clinical Features.
There are two basic patterns of starvation due to inadequate intake of calories and protein (Knight 1996).
▬
Wet type starvation features edema of the face, trunk, and limbs with pleural effusions and asci- tes. It is usually due to hypoproteinemia. The ca- loric intake in these types of starvation is some- times sufficient (as in kwashiorkor).
▬
Dry type starvation is characterized by loss of half the normal body mass and leg edema; the clinical picture features feeble pulse, hypotension, and cyanosis.
Pathology.
The principal autopsy findings include a negative relationship between body mass and length.
The gastrointestinal tract is usually empty and the parenchymal organs are atrophic. There is some- times a complete lack of macroscopically visible fat deposits in the abdominal walls and chest, with mas- sive loss of muscle mass. In the mesentery the amount of fat is reduced. Elevated levels of ketone bodies are found in urine and blood (Hawkins et al. 1971).
Neuropathology.
Lindenberg and Haymaker (1982) state that the brains of cachectic persons are often moist and soft. They harden poorly during fixation and easily shrink during dehydration and embed- ding. Despite the grave changes induced by malnu- trition in various other organ systems, the brains of cachectic adults exhibit surprisingly few changes.
The fully developed brain appears to be resistant to the effects of malnutrition (Harper and Butterworth 1997). MRI examinations of victims of anorexia ner- vosa (Deniker et al. 1986) and kwashiorkor (Gun- ston et al. 1992) show dilatation of the ventricles and
sulcal widening, apparently reversible phenomena.
During prolonged starvation the brain’s energy re- quirements are met in part by ketone body metabo- lism (Owen et al. 1967).
Malnourishment of the mother during gestation and/or lactation can result in delayed development of the fetal brain (Perez-Torrero et al. 2001) and lead to congenital brain malformations (Anderson et al.
1958) such as anencephaly, hydrocephalus, encepha- locele, and spinal bifida. If malnourishment persists beyond pregnancy to the early phase of postnatal development, it can cause delayed cell proliferation (Zamenhof et al. 1971; Torrero et al. 1999), dimin- ished neocortical dendrogenesis, a reduction in the number of dendritic spines (Salas 1980; Escobar and Salas 1995; Andrade et al. 1996), plus a drop in the synapse-to-neuron ratio (Bhide and Bedi 1985).
The development of child’s brain will be retarded as observed by several teams (Stoch and Smythe 1967;
Winick and Rosso 1969; Viteri 1981; Mize et al. 1984;
Listernick et al. 1985; Udani 1992); in particular, the brain mass will be reduced (Brown 1966). Specific al- terations associated with starvation during infancy and childhood are not described.
30.1.2
Vitamin Deficiencies
Malnourishment can also lead to vitamin deficien- cies, sometimes in combination with marasmus.
Thiamine deficiency is relatively common in alcoholics and is known to induce “beriberi” or Wernicke−Korsakoff syndrome (see Gropman et al.
1998 − see p. 376).
Niacin (nicotinic acid) deficiency is also encoun- tered in alcoholics (p. 380) as well as in tuberculosis patients. It can lead to “pellagra,” which is charac- terized by dermatitis, diarrhea, and dementia. Its ce- rebral symptoms include clouding of consciousness, confusion, and myoclonic jerks. Macroscopically the brain appears normal; histologically, neurons in the pontine nuclei and dentate nuclei of the cerebellum appear ballooned and exhibit a central chromatoly- sis (Harper and Butterworth 2002). The neurons also feature eccentric nuclei and a loss of Nissl substance.
The niacin deficiency may be a main symptom of child neglect (Piercecchi-Marti et al. 2004). In al- coholic populations most cases were reported with lesions seen especially in pontine nuclei and in the cerebellar dentate nuclei (Hauw et al. 1988).
Vitamin B12 deficiency affects patients with
Addison‘s pernicious anemia and diseases of the in-
testine. It can arise after gastric surgery. Among its
first clinical signs are bilateral sensory disturbances
in the feet, later in the hands and fingers. Mental
changes include depression, confusional states, and
neurasthenia. Macroscopically the brain is normal,
but the spinal cord may appear shrunken. Micro- scopically demyelination is noted in the white mat- ter of the posterior and lateral columns of the spinal cord.
Vitamin E deficiency is rare, being observed only after prolonged malabsorption. Clinically its symp- toms resemble those of Friedreich‘s ataxia. Neuro- pathologically the posterior columns, especially the fasciculus cuneatus, exhibit a marked axonal degen- eration.
30.1.3
Disturbances of Glucose Metabolism
Metabolic disturbances in diabetes mellitus are com- mon and can cause acute psychomotor alterations and acute death as well as chronic alterations of the nervous and vascular systems (Cameron et al. 2001).
Therefore, neurological complications in diabetes mellitus are frequent which affect sensorimotor, au- tonomic, and the central nervous system. Some 30%
of hospitalized and 20% of community-dwelling dia- betes patients have peripheral neuropathy; the annu- al incidence rate is approximately 2%. The primary risk factor is hyperglycemia.
The distal symmetric sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss.
Cardiac autonomic neuropathy may contribute to myocardial infarction, malignant arrhythmia, and sudden death. The pathology is multifactorial and involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation (Simmons and Feldman 2002; Duby et al.
2004). All contribute to microvascular disease and nerve dysfunction.
Autonomic neuropathy is a frequent feature of diabetic neuropathy and the source of many sig- nificant problems including postural hypotension, gastroparesis, diarrhea, constipation, neurogenic bladder, and male impotence (Greene et al. 1992;
Ross 1993). The neuropathologic alterations of au- tonomic ganglia have been extensively investigated in animal experiments and documented (Schmidt et al. 2003). The structural alterations, i.e., neuritic dystrophy expressed by markedly swollen axons and dendrites, are focused on prevertebral neuropatho- logical alterations of autonomic ganglia. A chronic involvement of the central nervous system will be induced by chronic or transient states of hyperglyce- mia/hypoglycemia as well as − secondarily − due to a vascularly caused reduction of cerebral blood flow.
The sequelae of permanent hypoglycemic or hyper- glycemic processes causing death will be described below.
30.1.3.1
Hypoglycemic Encephalopathy
Some basic principles associated with hypoglycemic encephalopathy are described elsewhere (Chap. 13, pp. 286 ff).
Pathophysiology.
Hypoglycemic encephalopathies can be caused by an insulin overdose, whether in- tentional (i.e., homicidal or suicidal) or accidental, or by failed gluconeogenesis in patients with hepatic disease. Neurological deficits in diabetics can result from vascular disorders (including changes in the blood−brain barrier) or other types of metabolic disturbances, including hyperglycemia, hyperosmo- lality, repeated hypoglycemic episodes, neuroendo- crine or neurochemical changes, acidosis, and keto- sis (Mooradian 1997).
The brain is supplied with energy by the oxida- tive metabolism of glucose. Four ATP molecules are produced by glycolysis, a further 38 by oxidative me- tabolism, for a total of 42 ATP molecules produced by each glucose molecule that totally combines with oxygen to form carbon dioxide and water. With few exceptions, the brain burns glucose as a fuel. The in- fant brain is somewhat protected against hypoglyce- mia by its ability to oxidize lactate (Thurston et al.
1983). During starvation, the brain utilizes ketone bodies circulating at elevated levels (Hawkins et al.
1971); the markedly hypoglycemic brain burns ke- tones as well (Ghajar et al. 1982).
It was once thought that both hypoxia- and hy- poglycemia-induced lack of oxidative metabolism could cause neuronal degeneration. It is now known that hypoglycemic cell changes can be prevented by pharmacological antagonists of NMDA excitatory re- ceptors (Wieloch 1985; Papagapiou and Auer 1990).
Clinical Features.
Hypoglycemia is associated with psychopathological changes ranging in severity from cognitive impairment to coma. The effects of hypo- glycemia can be ameliorated by optimizing blood glu- cose levels. In addition to acute neurological deficits, chronic deficits may also occur, diabetic neuropathy in particular. The secondary changes of diabetes, diabetes-associated hypertension, hypercholesterol- emia, and arteriosclerosis, are also possible.
Neuropathology.
Because both hypoglycemia and ischemia cause a selective neuronal necrosis in the cerebral cortex, hippocampus, and caudate nucleus (Auer et al. 1984), it can be very difficult to differen- tiate between these two insults in the human brain.
Animal experiments, however, have shown that they
can differ in their morphological sequelae (Auer and
Siesjö 1988 − see Chap. 13, pp. 287 f). Hypoglycemia
produces tissue alkalosis, whereas hypoxia causes
acidosis. Because hypoglycemia does not induce
acidosis, which is critical to the pathogenesis of cere- bral infarction, it does not result in the pan-necrosis (death of astrocytes as well as neurons, or infarction) seen in ischemia. Hypoglycemia differs from hypox- ia/ischemia in the following ways:
Hypoglycemia is associated with neither (1) infarc- tion nor (2) neuronal degeneration in the cerebellar cortex or brain stem (Auer and Sutherland 2002), (3) distribution of the neuronal necrosis in the cerebral cortex is superficial, a finding that contrasts with the selective neuronal necrosis in hypoxia/ischemia (see Chap. 13, pp. 286 ff), and (4) the granule cells of the dentate gyrus are subject to necrosis caused by the extracellular overflow of large quantities of aspartate, as the granule cells contain excitatory receptors.
There is also evidence of additional axonal injury as demonstrated by evoked compound action po- tentials (CAP): glucose withdrawal leads to delayed CAP failure (Brown et al. 2001). Dolinak et al. (2000) observed significant axonal injury in 13 cases of hy- poglycemic encephalopathy even in the absence of elevated intracranial pressure. In one case injured axons were distributed in a pattern like that seen in diffuse axonal injury.
30.1.3.2 Hyperglycemia
Hyperglycemic states can be as detrimental to the brain as hypoglycemic states, although only under hypoxic conditions. It is known that higher blood glucose levels can have a detrimental effect on the outcome of human global ischemia (i.e., cardiac ar- rest). Longstreth showed that mean glucose levels were 341 mg/100 ml blood in patients who did not awaken versus 262 mg/100 ml blood in patients who did awaken (Longstreth and Inui 1984). Of those patients who did awaken after cardiac arrest, mean blood glucose levels were 286 mg/100 ml in those with persistent neurological deficits versus 251 mg/100 ml in those without permanent neurological disability.
In focal ischemia (Pulsinelli et al. 1983), stroke (Ka- gansky et al. 2001) or near drowning (Ashwal et al.
1990) findings are similar. Brain hyperglycemia is associated with a reduction in cerebral O
2and glu- cose metabolism, giving rise to all the signs of toxic edema (cytotoxic hypoxidosis) (Bodechtel and Erb- slöh 1958). Morphologically, the associated selective parenchymal necrosis was stated to resemble that seen in hypoglycemia (see above). The author could observe one case of death caused by hyperglycemia which expressed a distinct necrosis of the putamen.
30.1.3.3 Diagnosis
Postmortem diagnosis of hypoglycemic encepha- lopathy is based on biochemical analysis of urine,
CSF, and vitreous humor. Patients with hyperglyce- mia have elevated blood levels of ketone and acetone:
diabetic ketoacidosis or non-ketotic hyperglyce- mic, hyperosmolar coma in patients with mild, of- ten non-insulin-dependent diabetes. At autopsy the sum of the glucose and lactic acid levels in CSF (or in vitreous humor) of individuals with hypoglycemia and hyperglycemia can be an indication of the glu- cose levels at the time of death (Traub 1969). Lactate and glucose sums >400 mg/dl in CSF and >450 mg/
dl in vitreous humor (Ritz and Kaatsch 1990) or
>500 mg/dl in CSF and >650 mg/dl in vitreous hu- mor (Kugler and Oehmichen 1986) may contribute to hyperglycemia-related acute death, whereas sums clearly <50 mg/dl are a sign of a fatal hypoglycemic situation. Because glycosylated hemoglobin (HbA1c) (Kugler and Oehmichen 1986; Winecker et al. 2002) and haptoglobin glycosylation (Ritz et al. 1996) re- main stable after death, their postmortem levels can provide information on glucose levels in the days im- mediately preceding death, and thus on the quality of diabetic therapy.
30.2
Dissociation of Water and Electrolyte Balance
30.2.1 Dehydration
Incidence.
As mentioned above, an adult can survive without water for about 10 days, children for less, es- pecially if the ambient temperature is high. In chil- dren, dehydration is often caused by fever, gastroen- teritis, or neglect, in the elderly by a lack of thirst.
Dehydration can result in an electrolyte imbalance, with an attendant risk of sudden death due to hyper- kalemic cardiac arrhythmia.
Clinical Features.
Both infants and adults suffering from dehydration have deeply sunken eyes reflecting the loss of water and orbital fat, dry internal organs and mucous membranes, and diminished skin tur- gor. The skin becomes dry and wrinkled and stays ridged when pinched due to the loss of subcutaneous fluid and fat. Infants exhibit a sunken fontanel.
Pathology.
As in life, the skin is wrinkled and dry and remains ridged when pinched between the fingers.
Internal organs appear shrunken (except the brain).
Feces in the rectum will be inspissated on account of
the dehydration. The intestinal lining may be ulcer-
ated by faecoliths. The diagnosis of dehydration can
be confirmed by clinical−biochemical analyses (Coe
1977, 1989) of the vitreous humor for the presence of
the so-called dehydration pattern of simultaneously elevated vitreous sodium (>155 mmol/l) and chloride (>135 mmol/l) combined with moderate elevation of urea nitrogen (400−1,000 mg/l).
Neuropathology (see p. 505).
The high hematocrit as- sociated with dehydration (Niaza et al. 1994) entails an elevated risk of stroke because the hyperviscosity of the hypercellular blood can diminish blood flow to levels liable to cause multiple small infarcts (To- hgi et al. 1978; Kirkham 1999). Dehydration-induced sinus thrombosis, invariably present if the veins are affected, can lead to thrombosis of superficial corti- cal veins. Initially the only change may be extreme congestion. Later, subarachnoid hemorrhage devel- ops with multiple hemorrhagic infarcts that cause considerable tissue destruction if they become con- fluent (Friede 1989). Patients are at risk of cerebral thrombosis of the large intracranial veins, which is fatal in most cases.
30.2.2
Hypernatremia
Clinical Features.
Hypernatremia is caused by extreme water loss (diabetes insipidus, diarrhea) or massive infusions of hypertonic solutions. It is associated with serum osmolality >330 mmol/kg and serum so- dium concentrations >160 mmol/l. The neurological manifestations, which include seizures, myoclonus, focal deficits and coma, are superimposed on the systemic signs of dehydration (see above).
Pathophysiology and Neuropathology.
Hyperna- tremic encephalopathy originates in the transudation of water from the intracellular milieu to extracellu- lar hyperosmolar compartments. The result is cell shrinkage and loss of brain volume, with stretching and even tearing of small bridging vessels anchored to the dura on the skull’s inner table. If tearing does occur, the resulting intracranial hemorrhage is a ma- jor complication that may account for the permanent sequelae of hypernatremic encephalopathy (Young and Truax 1979).
In 1959, Adams, Victor and Mancall described four patients with non-inflammatory demyelination in the central pons, two with a rapidly evolving flac- cid quadriplegia and two without symptoms (Adams et al. 1959). It is now common knowledge (p. 610) that pontine myelinolysis (see below) can develop after excessively rapid correction of chronic hypo- natremia (Brunner et al. 1990); however, this neuro- logical event is not recognized as a complication of hypernatremia when arising from a normonatremic baseline. Following the hypothesis that myelinoly- sis will occur after induction of a more significant osmotic gradient than when starting from a hypo-
natremic state, Soupart et al. (1996) succeeded in in- ducing severe demyelinating lesions in rats similar to the histologic changes observed in hyponatremia- related myelinolysis.
If the extracellular osmolality increases slowly, brain cells can adjust to their changing environment by augmenting concentrations of idiogenic osmoles, which are intracellular, osmotically active particles.
The osmoles consist mainly of amino acids (gluta- mate, glutamine, and aspartate) that prevent water from leaving the intracellular space. Remarkably, during chronic hyperosmolality the intracellular id- iogenic osmoles may induce acute water intoxication if the extracellular space becomes suddenly normo- osmolar due to precipitous rehydration with hypo- tonic fluids.
30.2.3
Hyponatremia and Water Intoxication
Hyponatremia is defined as the drop of serum so- dium levels from a normal level of about 140 mmol/l to below 125 mmol/l. Adrogué and Madias (2000) recently surveyed the causes and consequences of hyponatremia. It is associated with normal, low or high tonicity (Gennari 1998). Hypotonic hyponatre- mia represents a relative excess of water in relation to existing sodium stores whether low, normal or high. Water retention usually results from condi- tions that impair renal water excretion. If excretion is normal or near normal, excessive water intake is the most common cause (primary polydipsia). The importance of hyponatremia is consistently under- estimated. Rat experiments on acute and chronic hyponatremia showed that major determinants of mortality were gender, age, and the cerebral effects of vasopressin (Arieff et al. 1995).
Incidence.
The literature on hyponatremia consists
mainly of individual case reports. A case study on
fatal child abuse by water intoxication was published
by Arieff and Kronlund (1999 − see below). Athletes
are especially prone to excessive water intake to pre-
vent dehydration and exertional heat illness, which
has resulted in a rise in the number of hyponatremia
cases (Gardner 2002). Keating et al. (1991) reviewed
the cases of 34 children treated at St. Louis (Missouri)
Children’s Hospital between 1975 and 1990 for water
intoxication being manifestly the result of abuse. In
postmenopausal women chronic symptomatic hy-
ponatremia is a major contributor to morbidity and
mortality. Intravenous sodium chloride treatment
produced significantly better outcomes than fluid
restriction when given for respiratory insufficiency
(Ayus and Arieff 1999).
Pathogenesis.
Although it is the most common elec- trolyte disorder, hyponatremia rarely results from excessive water intake unless the kidney cannot ex- crete free water, or because of protein retention in patients with liver cirrhosis or who have undergone orthotopic liver transplantation (Papadakis et al.
1990; Wszolek et al. 1999). Hypotonic hyponatremia mainly manifests as CNS dysfunction and increases in severity with the amount and rapidity of the de- cline in serum sodium levels. It causes water to enter the brain, resulting in brain edema and intracranial hypertension and possible brain injury. Fortunate- ly, the solutes leave brain tissues within a matter of hours, thus inducing water loss and ameliorating the brain swelling (Verbalis and Gullans 1991).
Pathology and Clinical Features.
According to Coe (1977), water intoxication is marked by a specific pattern of low vitreous sodium (<130 mmol/l), low chloride (<105 mmol/l), and relatively low potassium (<15 mmol/l). Arieff and Kronlund (1999) described three cases of fatal child abuse by forced water intake (>6.0 l). All of the victims presented to hospital with hypoxemia and hyponatremia; they experienced sei- zures, emesis, and coma. None of the three children were treated for hyponatremia because the forced water intoxication was not revealed to medical per- sonnel. At autopsy all three were found to have aspi- ration pneumonia and cerebral edema.
A recent investigation (Saeed et al. 2002) gives a catamnestic review of 42 adult patients suffering severe hyponatriemia. Nine patients had central ner- vous symptoms and four of these patients died in hospital. The authors recommended that the diag- nosis requires an accurate drug history, clinical ex- amination, and assessment of fluid volume, plus the measurement of urinary electrolytes and osmolality in a spot urine sample. Neuropathological findings are not described.
Neuropathology.
The CNS features a pronounced brain edema.
30.2.4
Hyponatremia
and Central Pontine Myelinolysis
Central pontine myelinolysis (CPM) is a rare com- plication of hyponatremia characterized by non- inflammatory demyelination. It has been shown in controlled experimental conditions to be an osmotic instability of myelin reproducible after rapid correc- tion of hyponatremia (Lien et al. 1991; Laureno and Karp 1997).
Pathogenesis.
CPM was originally assumed to be almost exclusively a consequence of chron-
ic alcohol abuse, since it is often associated with Wernicke−Korsakoff syndrome. But many non-alco- holics are also affected, usually patients with severe liver disease (Goebel and Zur 1972), especially after liver transplantation (Estol et al. 1989), severe burns (McKee et al. 1988), severe electrolyte disorders, mal- nutrition, or anorexia. It can also be caused by tu- bulopathy, water intoxication, or abuse of diuretics in individuals with anorexia nervosa (Amann et al.
2001). The signal pathogenetic factor is over-correc- tion of chronic hyponatremia with hypertonic saline (Norenberg et al. 1982; Soupart et al. 2000). This hy- pothesis has been questioned though by a number of authors (Bird et al. 1990; Papadakis et al. 1990; Ashra- fian and Davey 2001; Leens et al. 2001) and alternative hypotheses proposed, such as hypophosphatemia (Peters et al. 1993), but the central pathogenetic factor from animal and human studies is rapid correction of hyponatremia (Klineschmidt-DeMasters and Noren- berg 1981, 1982; Norenberg et al. 1982).
Incidence.
Pathological−anatomical studies indicate that this disease picture is relatively rare. CT and MRI techniques meanwhile allow detection of more cases during early stages as well as observation of complete recovery (Wakui et al. 1991).
Clinical Features.
The clinical features include spastic tetraparesis, pseudobulbar paralysis, and locked-in syndrome and are a reflection of damage to the de- scending motor tracts. MRI of the brain reveals pro- longed T1 and T2 relaxation in a characteristically shaped area of the central pons. The extent of recov- ery varies, ranging from substantial to none (Pirzada and Ali 2001).
Neuropathology (Fig. 18.5 – p.380).
The localization of
the myelinolysis is highly characteristic. It usually
occurs in the center of the base of the pons, extend-
ing rostrally from just beneath the midbrain through
the upper two-thirds of the pons. The myelinolysis
occurs symmetrically about the midline rostrocau-
dal axis and can be easily recognized on myelin-
stained sections as a sharply demarcated area of pal-
lor within the basis pontis (Harper and Butterworth
1997). The first sign is a demyelination process with
preservation of axons followed by an inflamma-
tory reaction with conspicuous preservation of the
neurons. The myelinosis is usually accompanied by
osmosis-induced pontine glial cell swelling and cell
death (Ashrafian and Davey 2001). Within freshly
demyelinated lesions the GFAP immunolabeling of
astrocytic cytoplasm is drastically reduced. In both
recent and old lesions, immunostaining of vimentin
reveals differential intracytoplasmic decoration of
dystrophic and hypertrophic astrocytes (Gocht and
Lohler 1990). Other microscopic alterations depend
on the age of the lesion. Very severe lesions exhibit
complete necrosis of the central zone. Extrapontine lesions can occur in the thalamus, striatum, cerebel- lum, and in the cerebral white matter (Wright et al. 1979; Goldman and Horoupian 1981; Estol et al.
1989). Extrapontine demyelination without actual central pontine myelinolysis has now been described as well (Okeda et al. 1986).
30.3
Hepatic Encephalopathy
Hepatic encephalopathy exhibits both neurologic and psychopathologic symptoms. One characteristic neuropsychiatric feature in the majority of patients is the potential for complete recovery. The condi- tions under which hepatic encephalopathy may arise (see Harper and Butterworth 2002) were summed up by the Working Party at the 11th World Congress of Gastroenterology in Vienna (1998 − see Ferenci et al.
2002): (1) acute fulminant hepatic failure, (2) por- tal-systemic congestion (bypass of the liver related to portosystemic shunts without intrinsic liver dis- ease), and (3) chronic liver disease (cirrhosis, portal hypertension or familial hepatolenticular degenera- tion = Wilson‘s disease), (4) Reye‘s syndrome, which constitutes a special form of hepatic encephalopathy and will be described below, and (5) bilirubin en- cephalopathy, which is discussed in Part V, “Pediat- ric Neuropathology” (pp. 452 ff).
Clinical Features.
The clinical features differ between patients with symptomatic encephalopathy and pa- tients with minimal encephalopathy, which has no discernible symptoms of brain dysfunction (Ferenci et al. 2002). The neurological findings in symptomatic encephalopathy usually pertain only to the patient’s motor and mental status. Characteristic of the al- tered mental status is impairment of the sleep−wake cycle, of attention, cognition, orientation, and con- sciousness. The neurologic status features dysar- thria, increase in tone, hypomimia, slow or clumsy rapidly alternating movements, tremor, ataxia, in- creased deep tendon reflexes, and impairment of posture or postural reflexes. Differential diagnosis must exclude concomitant neurological influences such as Wernicke’s disease, other types of metabolic disease, and drug intoxication (alcohol, sedatives, etc.). The symptoms of minimal encephalopathy are subclinical and include euphoria or anxiety, lack of awareness, shortened attention span, and impaired performance of addition (Ferenci et al. 2002).
Pathophysiology.
Hepatic encephalopathy is caused by elevated levels of endogenous neurotoxins. It has various possible causes, prominent among them be- ing hyperammonemia, altered amino acid ratios, an
increase in the aromatic amino acid to branched- chain amino acid ratio, plus benzodiazepine ex- cesses in certain brain areas (Mullen and Kaminsky- Russ 1996; Butterworth 1997). The prime candidate for the causative neurotoxin in hepatic encephalopa- thy is ammonia (Butterworth 2000; Felipo and But- terworth 2002). Consequently, astrocytes − where ammonia is mainly metabolized − probably play a key, perhaps a dominant, role in the pathogenesis of hepatic encephalopathy. Norenberg (1994) hypoth- esized that toxins affect the astrocytes, while abnor- mal glial function disturbs the microenvironment and glial−neuronal interactions. Acting together, these factors lead to disordered neuronal activity.
The evidence today suggests that changes in neuro- transmission may also contribute to this type of en- cephalopathy (Butterworth 2001). Such changes may be due to a depletion of cerebral energy (Rao and Norenberg 2001). The only brain cells that contain glutamine synthetase for ammonia removal are as- trocytes, which thus have a high affinity for the glu- tamate transporters EAAT-1 and EAAT-2 as shown in the rat forebrain. The macroscopic brain changes include a cerebral edema and intracranial hyperten- sion. Alterations also occur in the astrocytes them- selves (see below).
30.3.1
Fulminant Hepatic Failure
Rapid onset of severe inflammatory or necrotic liver disease leads precipitately to stupor and coma, or to delirium, mania or seizures. Cytotoxic brain swell- ing is the salient pathological feature, with an atten- dant risk of cerebellar tonsillar herniation. Hernia- tion can give rise to secondary hemorrhages in the brain stem. Hemorrhagic diathesis induces multi- focal hemorrhages and hypoxia secondary to brain swelling.
30.3.2
Chronic Liver Disease and Portal-Systemic Bypass
Patients with cirrhotic liver disease slowly develop hepatic encephalopathy. Symptoms start with al- tered sleep patterns and progress through asterixis to stupor and coma. The liver cirrhosis generates a portal hypertension and in some cases a transjugular intrahepatic portosystemic stent shunt (Butterworth 2000). The clinical symptoms are often preceded by constipation, a dietary protein overload, or gastroin- testinal bleeding.
Neuropathology.
The brain appears macroscopically
normal. It is disputed whether cirrhosis alone can
induce brain atrophy in the absence of simultaneous chronic alcohol abuse (see Lee et al. 1979 versus Acker 1986). Microscopically this form of encephalopathy is characterized by astrocytic (rather than neuronal) alterations termed Alzheimer II astrocytosis (astropa- thy). The astrocytes possess pale watery and enlarged nuclei with scant chromatin distributed around the periphery; they often have a distinct nucleolus. Expres- sion of GFAP is unchanged or decreased depending upon the region of the brain (Norenberg et al. 1990).
For example, there is decreased GFAP immunolabel- ing of cerebral cortical astrocytes in the cerebrum of chronic liver failure patients (Sobel et al. 1981) or following end-to-side portocaval anastomosis in rats (Norenberg 1977). GFAP immunolabeling of cerebel- lar Bergmann glia is unchanged (Kril et al. 1997).
Alzheimer II type astrocytes are seen mainly in deep layers of the cerebral cortex, in Bergman glial cells of the cerebellum, in the basis pontis, striatum, thalamus, globus pallidus, inferior olives, and den- tate nucleus (Harper and Butterworth 2002). GFAP is not expressed by processes of Alzheimer type II or the perikaryon (Sobel et al. 1981; Norenberg 1990;
Belanger et al. 2002). The nuclei in some cases be- come lobulated and are located in the gray matter, especially in the substantia nigra, dentate nucleus, and globus pallidus (Norenberg 1994). Alzheimer type II glia are not specific for hepatic encephalopa- thy, but occur in other metabolic encephalopathies such as hypocapnia, uremia, and in the early stages of anoxia and hypoglycemia, especially in infants.
The common pathogenetic factor appears to be the elevated blood or brain ammonia (Norenberg 1994).
30.3.3
Familial Hepatolenticular Degeneration (Wilson’s Disease)
Wilson‘s disease is a familial metabolic disorder trans- mitted in an autosomal recessive manner and charac- terized by liver cirrhosis in association with neuronal degeneration in the striatum. The responsible gene ap- pears to code for a copper-transporting P-type ATPase and has been mapped to chromosome 13 (Bull et al.
1993). Starting at birth, patients with Wilson‘s disease have 10 to 50 times normal copper levels in the liver and a caeruloplasmin deficiency in the blood. The first clinical symptoms appear in the 5th year of life. Neu- rological symptoms include progressive rigidity, trem- or, dysarthria, dysphagia, and dementia. Pathognomic of Wilson’s disease is the so-called Kayser−Fleischer ring of brown pigmentation in the cornea.
Neuropathology.
The ventricles are symmetrically dilated, especially close to the striatum, and the stri- atum appears brown or brick-red in color. The puta- men often shows cavitation. Microscopically there is
a proliferation of Alzheimer type II astrocytes and neuronal loss in the putamen, the globus pallidus, caudate nucleus, and thalamus. There is also an in- crease in the number of Opalski cells (no processes, large perikaryon, small nucleus) and Alzheimer type I cells (large, multinucleated astrocytes). Iron pig- ment is evident in macrophages. Enhanced pericap- illary accumulation of copper is characteristic.
30.3.4
Reye’s Syndrome
Reye‘s syndrome is marked by an association be- tween encephalopathy and hepatomegaly. This is not a rare syndrome. The Center for Disease Control, Atlanta/Georgia, documented 655 cases in the years 1977 and 1978 alone, 32% of which were fatal (Starko et al. 1980). It does not appear to have a single cause, likely causes including toxic, infectious or metabolic insults. Short- and medium-chain fatty acids are thought to play a major role in the pathogenesis, with injury to the mitochondria of the liver producing the liver symptoms (Mamunes et al. 1974). Encephalopa- thy has been attributed among other causes to a hy- perammonemia (DeLong and Glick 1982).
The clinical manifestations begin with vomiting, personality change, and somnolence progressing to convulsions and coma. Children between the ages of 2 and 16 are the main victims, although a few cases involving adults have been reported (Van Coster et al. 1991). Elevated levels of transaminases in blood is common, as is hypoglycemia (Reye et al. 1963).
Neuropathology.
The brain alterations associated with Reye’s syndrome feature a marked cytotoxic brain edema with distinct swelling of astrocytic foot processes (Blisard and Davis 1991). Frequent find- ings include acute, multifocal ischemic changes in the cerebral cortex, cerebellum, hippocampus, and basal ganglia (Pedal et al. 1984). The liver undergoes fatty degeneration. Electron microscopic demonstra- tion of anomalous liver mitochondria is regarded as constituting proof of Reye’s syndrome.
30.4
Uremic Encephalopathy
A number of acquired and genetically determined
diseases are thought to affect the brain and kidney,
among them vasculitides, paraproteinemias, micro-
angiopathies, and von Hippel−Lindau disease. Inde-
pendent of these diseases, uremic encephalopathy
can also be caused by renal failure, which induces
a rise in substances normally eliminated with the
urine. Acute kidney failure can have a profound ef-
fect on the nervous system. Uremia affects both the central and peripheral nervous systems.
Pathophysiology.
Uremia with accumulation of toxic substances causing encephalopathy can be attributed to a broad spectrum of pathogenic diseases, chronic renal diseases, or to acute renal failure as well. The four guanidino compounds known to accumulate in uremia are creatinine, guanidine, guanidinosuccinic acid, and methylguanidine. These substances have been shown in animal studies to induce behavioral alterations and long-lasting generalized convulsions (D’Hooge et al. 1992). In humans, uremia is associat- ed with decreased brain oxygen consumption; in ro- dent models of acute renal failure, with diminished brain energy consumption (Mahoney et al. 1984). It has been proposed that encephalopathy is caused by derangements of amino acids (mainly glycine, glu- tamine, aromatic and branched-chain amino acids) plus a neurotransmitter imbalance (mainly GABA, dopamine, serotonin) (Biasioli et al. 1986). Encepha- lopathy has also been attributed to an extensive neu- roendocrine disturbance (Handelsman and Dong 1993). Because uremia-associated neuropsychiatric symptoms are improved by either medical suppres- sion of parathyroid hormones or parathyroidectomy (Cogan et al. 1978), it is also thought that parathy- roid hormone is a CNS uremic toxin (Fraser 1992).
Moreover, as many as 40% of uremic patients re- ceive ciclosporin, which may result in neurological side-effects. Five per cent of patients with uremia develop nerve injuries during renal transplantation and up to 45% of transplant patients suffer CNS in- fections, often fungal in type, that end in death (Burn and Bates 1998).
Classification.
Four different types of encephalopa- thy are distinguished (Rob et al. 2001):
▬
Uremic encephalopathy, a complication of uremia that responds well to dialysis.
▬
Dialysis encephalopathy syndrome (see below), which results from acute aluminum intoxication associated with aluminum-containing dialysate.
▬
Dialysis-associated encephalopathy/dementia, which invariably involves elevated serum alu- minum levels.
▬
Age-related vascular dementia, in particular, is as common among patients on long-term dialysis as among the general population.
Clinical Features.
Uremic encephalopathy features signs of depressed brain function manifested as cog- nition and memory disturbances, and can progress over time to delirium, convulsions, and coma. Peri- ods of dialysis may initially aggravate the encepha- lopathy, and are related to changes in metabolic states associated with ionic changes or diminished synaptic function. Symptoms of global cerebral involvement
are also seen, including agitation and fluctuating disturbances of consciousness accompanied by hy- perpnea (Kussmaul or Cheyne-Stokes type), multifo- cal myoclonus, hyperreflexia, asterixis, tremor, and brain stem signs with various types of nystagmus and muscle tone abnormalities (Kunze 2002). Uremic en- cephalopathies are marked by elevated serum creati- nine, potassium, phosphates, as well as by metabolic acidosis and hypocalcemia. The peripheral nervous system can also be affected by renal failure, display- ing a neuropathy with a predilection for axons that are large in diameter (Burn and Bates 1998; Kunze 2002). Dialysis or transplantation can reverse these processes. The myopathy accompanying renal failure resembles that of primary hyperparathyroidism and osteomalacia and is frequently associated with bone pain and tenderness (Burn and Bates 1998).
Pathology.
Uremia/renal insufficiency and the un- derlying renal disease characterize the pathology. In cases with uncertain diagnosis, the uremia pattern (Coe 1977) should be assessed: marked elevations of vitreous and serum urea levels and creatinine with- out a significant rise in sodium and chloride values are specific to uremic encephalopathy.
Neuropathology.
The main neuropathological find- ing of reversible cerebral edema is associated with rapid dialysis. Despite the steep drop in plasma urea levels, the retention of brain urea accounts for the rise in brain water (Silver 1995). Patients with chronic renal failure and hypertension, or patients receiving conservative treatment or hemodialysis were found to suffer from cerebral atrophy (Savazzi et al. 2001;
Savazzi and Cusmano 2002). Subdural hemorrhages were found in 1−3% of 400 patients dying of chronic renal failure (Fraser and Arieff 1988). Variably pro- nounced, usually generalized neuronal degeneration has been reported to strike perivascular areas of de- myelination and necrosis. The affected brain areas include the subcortical nuclei, cerebral cortex, the cerebellum, and nuclei of the brain stem. Alzheimer type II astrocytes are common (Norenberg 1994). In one case the affected internal capsules, periventricu- lar white matter, and bilateral basal ganglia were hypodense on CT (Okada et al. 1991). Isolated cases have exhibited Wernicke’s encephalopathy (Jagadha et al. 1987; Ihara et al. 1999) or − in patients with he- molytic uremic syndrome − involvement of the basal ganglia (Barnett et al. 1995; Theobald et al. 2001).
30.4.1
Dialysis Encephalopathy
Dialysis itself can induce neurological disorders such
as Wernicke‘s encephalopathy, disequilibrium syn-
drome, and subdural hemorrhage. In patients with
chronic renal failure the use of long-term hemodi- alysis is associated with endemic lethal encephalopa- thy attributable to the high aluminum levels (Alfrey et al. 1976) in the dialysate. Modern techniques of water purification, however, are now able to avert such acute intoxication. Dialysis encephalopathy is characterized clinically by headache, nausea, EEG abnormalities, emesis, blurred vision, tremor, muscle twitching, hypertension, asterixis, seizures, dementia, disorientation, and myoclonic jerks. The clinical and neuropathological features of dialysis encephalopathy have led some authors to postulate an association between dialysis dementia, alumi- num intoxication, and Alzheimer’s disease.
Neuropathology.
Biochemically, dialysis dementia features a conspicuous increase in the brain’s alu- minum content (see Chap. 17, pp. 339 f). Reusche (2002) used a simple and effective method for dem- onstrating neurofibrillary tangles and senile plaques to show that aluminum encephalopathy exhibits identical morphologic features to those found in Al- zheimer's disease. He did not however provide any evidence of elevated aluminum levels in the brains of Alzheimer's patients (Reusche 1997).
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