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Neurology_Adams. Often there are other members of the family with a different autoimmune disease. It has been the myoclonic aspect of the encephalopathy, a feature of all of the cases we have observed, which has usually led to consideration of this diagnosis. It is not uncommon for such cases to be mistaken for Creutzfeldt-Jakob disease (subacute spongiform encephalopathy). Early descriptions of the illness included a pleocytosis of the spinal fluid and white matter lesions, but we have not consistently noted these abnormalities. What limited pathology there is, in a case studied after 5 months of illness, has shown only nonspecific activation of microglia cells (Perrot et al).


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Neurology_Adams. Treatment The encephalopathic symptoms and high titers of antithyroid antibodies respond well to steroid therapy (see Chong et al). In the case reported by Newcomer and associates, a rapid reversal of thyrotoxic coma (and corticospinal signs) was effected by plasma exchange, in parallel with a reduction in T4 and T3 levels, and similar results were reported by Boers and Colebatch. The circulating antibodies and the response to corticosteroids and plasma exchange implicate an immune pathogenesis, perhaps similar to paraneoplastic limbic encephalitis (see “Encephalomyelitis Associated With Carcinoma and Limbic Encephalitis” in Chap. 30) such as the encephalitis that may accompany ovarian teratoma, and to lupus.


Neurology_Adams

Neurology_Adams. As a rule, in the myxedematous patient, cognitive activity is slowed; in exceptional cases, there is a significant confusional state or stupor. When such changes have been observed, we have noted drowsiness, inattentiveness, and apathy as early features. In 2 cases observed by our colleagues, the somnolence was so extreme that the patients could not stay awake long enough to be fed or examined. They were in a state of hypothermic stupor but exhibited no other neurologic abnormality. In extreme form, the state progresses to “myxedema coma.” This state is often precipitated by stresses, particularly surgery and sepsis, mainly in the elderly. Hypothermia, hyponatremia and elevation of serum creatine kinase (CK) concentration, hypoventilation, and elevation of the CSF protein can be expected. The clinical state and laboratory abnormalities are reversed within a few days by thyroid medication. The treatment of myxedema coma has several refined aspects, including the need to administer


Neurology_Adams

Neurology_Adams. The clinical state and laboratory abnormalities are reversed within a few days by thyroid medication. The treatment of myxedema coma has several refined aspects, including the need to administer thyroid hormone cautiously; details can be found in Harrison’s Principles of Internal Medicine.


Neurology_Adams

Neurology_Adams. Hypothyroidism is associated with a number of distinctive myopathic disturbances, which are discussed in Chap. 45. The ataxia and peripheral neuropathy that are sometimes observed in patients with myxedema were described earlier and in Chap. 43. This form of severe intrauterine hypothyroidism (in mother and fetus) or postnatally as a hereditary or acquired thyroid disease, is probably the most frequent and potentially preventable and correctable metabolic cause of encephalopathy in the world. Although the condition is most common in goitrous regions where there is a lack of iodine, it may also be the result of any of several genetically determined defects in thyroxin synthesis that have come to light (Vassart et al). In areas of endemic cretinism, additional factors may be operative, such as the widespread ingestion of cassava, which contains a toxic goitrogen that inhibits the uptake of iodine by the thyroid.


Neurology_Adams

Neurology_Adams. The symptoms and signs of congenital thyroid deficiency are not usually recognizable at birth but become apparent only after a few weeks; more often the diagnosis is first made between the 6th and 12th months of life. Physiologic jaundice tends to have been severe and prolonged (up to 3 months), and this, along with widening of the posterior fontanelle and mottling of the skin, should raise suspicion of the disease.


Neurology_Adams

Neurology_Adams. Two types of early life hypothyroidism are recognized—sporadic and endemic. The sporadic type occurs occasionally in developed countries (less than once in 4,000 live births) and is a consequence of a congenital metabolic or anatomic disorder of the thyroid gland. At birth, the gland is either absent or represented by cysts, indicating a failure of development or a destructive lesion. In the sporadic form, in the latter part of the first year, stunting of growth and delay in psychomotor development become evident. Untreated, the child is severely developmentally delayed but placid and good natured; such children sleep contentedly for longer periods than normal children. Sitting, standing, and walking are delayed. Movements are slow, and if tendon reflexes can be obtained, their relaxation time is clearly delayed. The body temperature is low, and the extremities are cold and cyanotic. Although the head is small, the fontanelles may not close until the sixth or seventh year, and there


Neurology_Adams

Neurology_Adams. time is clearly delayed. The body temperature is low, and the extremities are cold and cyanotic. Although the head is small, the fontanelles may not close until the sixth or seventh year, and there is delayed ossification. This type of hypothyroidism is preventable by treatment with thyroid hormone.


Neurology_Adams

Neurology_Adams. Endemic cretinism is most common in developing countries, with an estimated incidence in some areas of 5 to 15 percent. DeLong and colleagues, on the basis of epidemiologic surveys mainly in western China, have distinguished 2 forms of endemic cretinism: neurologic and myxedematous. The occurrence of the 2 different types is governed by the timing, duration, and severity of the iodine deficiency (Thilly et al).


Neurology_Adams

Neurology_Adams. The neurologic form of neonatal myxedema is characterized by varying degrees of deaf-mutism or lesser degrees of hearing loss, dysarthria, proximal limb and truncal rigid-spastic motor disorder involving mainly the lower extremities, and cognitive impairment of a characteristic type. In the most severely affected, there is also strabismus, kyphoscoliosis, underdevelopment of leg muscles, and frontal lobe release signs. Bone age, head size, and height are normal and there are none of the coarse facial features of the myxedematous form. In the myxedematous form of endemic cretinism, short stature, microcephaly, coarse facial features, and delayed psychomotor development are the main features. There is no deafness or spastic rigidity of the limbs. In typical instances, the face is pale and puffy; the skin dry; the hair coarse, scanty, and dry; the eyelids thickened; the thickened lips parted by the enlarged tongue; the forehead low; and the base of the nose broad. There are fat pads


Neurology_Adams

Neurology_Adams. puffy; the skin dry; the hair coarse, scanty, and dry; the eyelids thickened; the thickened lips parted by the enlarged tongue; the forehead low; and the base of the nose broad. There are fat pads above the clavicles and in the axillae. The abdomen is protuberant, often with an umbilical hernia, and the head is small.


Neurology_Adams

Neurology_Adams. DeLong and others attribute neurologic cretinism to a lack of available iodine in the mother and fetus during the second and third trimesters of pregnancy; neither mother nor fetus produces thyroxine. It is during the latter part of the second trimester, when the cochleas and the neuronal population of the cerebral cortex and basal ganglia are forming, that these structures suffer irreparable damage from lack of thyroid hormone. The effects of this midfetal hypothyroidism and iodine deficiency cannot be corrected by giving thyroid hormone at birth and thereafter. It can be prevented only by providing iodine therapy to the mother before and during the first trimester of pregnancy (Cao et al). The myxedematous form of cretinism is more likely to occur from lack of thyroid hormone in the late second and the third trimesters.


Neurology_Adams

Neurology_Adams. The congenital mental disorder ranges from apathy and absence of social interaction to an alert, cooperative state but slowness in higher-order thinking and verbal facility is always evident. The status of the thyroid gland varies; among patients with the neurologic features of cretinism, about half have goiters or have palpable glands; in the rest, the glands are atrophied; practically all patients with myxedematous cretinism are athyrotic. Although typical examples of neurologic and myxedematous hypothyroidism are readily distinguished, both types may exist in the same endemic area, and stigmata of both forms may be recognized in the same individual. The QRS complex of the ECG is of low voltage; the EEG is slower than normal, with less alpha activity; the CSF contains an excess of protein (50 to 150 mg/dL); and the serum T3 and T4, protein-bound iodine, and radioactive iodine uptake are all subnormal. Serum cholesterol is increased (300 to 600 mg/dL).


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Neurology_Adams. At autopsy the brain of neurologic cretinism, although small, is normally formed, with all central and brainstem structures and cortical sulcation intact. A reduction in number of nerve cells was described by Marinesco, especially in the fifth cortical layer, but others have not confirmed this finding. The use of Golgi and other silver techniques has shown decreased interneuronal distances (packing density is increased, as in the immature cortex) where there is a deficiency of neuropil. The latter change is because of a poverty of dendritic branchings and crossings, and presumably there is a decrease of the synaptic surfaces of cells (Eayrs). Thyroid hormone appears to be essential, not for neuronal formation and migration but for dendritic–axonal development and organization.


Neurology_Adams

Neurology_Adams. There is substantial evidence that the administration of iodized salt or iodinated vegetable oil or iodide tablets to populations of women who are at risk of iodine deficiency before and during the first trimester of pregnancy prevents sporadic and endemic cretinism. Treatment begun during the second trimester protects the fetal brain to a varying degree. Treatment that is started after the beginning of the third trimester does not improve the neurologic status, although head growth and statural development may improve slightly (Cao et al). In sporadic cretinism, if the condition is recognized at birth and treated consistently with thyroid hormones, height and mental development can be stimulated to normal or near-normal levels. The extent of recovery depends on the severity and duration of intrauterine hypothyroidism, that is, its duration before treatment was begun and the adequacy of therapy. In most patients, some degree of cognitive impairment persists throughout life.


Neurology_Adams

Neurology_Adams. This term was introduced by Rothermich and von Haam in 1941 to describe what they considered to be a fairly uniform clinical state in patients with acute abdominal symptoms referable to pancreatic disease, mainly pancreatitis. The encephalopathy, as they described it, consisted of an agitated, confused state, sometimes with hallucinations and clouding of consciousness, dysarthria, and changing rigidity of the limbs—all of which fluctuated over a period of hours or days. Coma and quadriplegia have been reported. At autopsy, a variety of lesions have been described; two cases have had central pontine myelinolysis and others have had small foci of necrosis and edema, petechial hemorrhages, and “demyelination” scattered through the cerebrum, brainstem, and cerebellum. These have been uncritically attributed to the action of released lipases and proteases from the diseased pancreas (see review of this subject by Sharf and Levy).


Neurology_Adams

Neurology_Adams. The term pancreatic encephalopathy is now more often applied to a depressive illness that seems to occur with disproportionate frequency before the symptoms of a pancreatic cancer become apparent. More common in our experience are numerous cases of pancreatic cancer and sequential cerebral emboli from nonbacterial thrombotic (marantic) endocarditis. The status of pancreatic encephalopathy, in the authors’ opinion, is uncertain. Pallis and Lewis also express reservations and suggest that before such a diagnosis can be entertained in a patient with acute pancreatitis, one must exclude delirium tremens, shock, renal failure, hypoglycemia, diabetic acidosis, hyperosmolality, and hypocalcemia or hypercalcemia—any one of which may complicate the underlying disease. Other cases conform to the encephalopathy of multiorgan failure, discussed earlier. Adams RD, Foley JM: The neurological disorder associated with liver disease. Res Publ Assoc Res Nerv Ment Dis 32:198, 1953.


Neurology_Adams

Neurology_Adams. Adams RD, Foley JM: The neurological disorder associated with liver disease. Res Publ Assoc Res Nerv Ment Dis 32:198, 1953. Adams RD, Victor M, Mancall EL: Central pontine myelinolysis. Arch Neurol Psychiatry 81:154, 1959. Aikawa N, Shinozawa Y, Ishibiki K, et al: Clinical analysis of multiple organ failure in burned patients. Burns Incl Therm Inj 13:103, 1987. Alfrey AC, Legendre GR, Kaehny WD: The dialysis encephalopathy syndrome: Possible aluminum intoxication. N Engl J Med 294:184, 1976. Ames A, Wright RL, Kowada M, et al: Cerebral ischemia: II. The no-reflow phenomenon. Am J Pathol 52:437, 1968. Arieff AI: Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women. N Engl J Med 314:1529, 1986. Arrich J, Holzer M, Havel C, et al: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2:4128, 2016.


Neurology_Adams

Neurology_Adams. Arrich J, Holzer M, Havel C, et al: Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev 2:4128, 2016. Auer RN: Progress review: Hypoglycemic brain damage. Stroke 17:699, 1986. Austen FK, Carmichael MW, Adams RD: Neurologic manifestations of chronic pulmonary insufficiency. N Engl J Med 257:579, 1957. Basile AS, Hughes RD, Harrison PM, et al: Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med 325:473, 1991. Bass NM, Mullen KD, Sanyal A, et al: Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362:1071, 2010. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557, 2002. Bhatia MP, Brown P, Gregory R, et al: Progressive myoclonic ataxia associated with coeliac disease. Brain 118:1087, 1995.


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Neurology_Adams. Bhatia MP, Brown P, Gregory R, et al: Progressive myoclonic ataxia associated with coeliac disease. Brain 118:1087, 1995. Boers PM, Colebatch JG: Hashimoto’s encephalopathy responding to plasma-pheresis. J Neurol Neurosurg Psychiatr 70:132, 2001. Bolton CF, Young GB: Neurological Complications of Renal Disease. Boston, Butterworth, 1990. Bolton C, Young GB, Zochodne DW: The neurological complications of sepsis. Ann Neurol 33:94, 1993. Booth CM, Boone RH, Tomlinson G, Detsky AS: Is this patient dead, vegetative, or severely impaired? JAMA 291:870, 2004. Brain L, Jellinek EH, Ball K: Hashimoto’s disease and encephalopathy. Lancet 2:512, 1966. Burcar PJ, Norenberg MD, Yarnell PR: Hyponatremia and central pontine myelinosis. Neurology 27:223, 1977. Burn DJ, Bates D: Neurology and the kidney. J Neurol Neurosurg Psychiatry 65:810, 1998. Butterworth RF, Giguiere JF, Michaud J, et al: Ammonia: Key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 6:1, 1987.


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Neurology_Adams. Butterworth RF, Giguiere JF, Michaud J, et al: Ammonia: Key factor in the pathogenesis of hepatic encephalopathy. Neurochem Pathol 6:1, 1987. Cao X-Y, Jian GX-M, Dou Z-H, et al: Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 331:1739, 1994. Castillo P, Woodruff B, Caselli R, et al: Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 63:197, 2006. Cavanagh JB: Liver bypass and the glia. Res Publ Assoc Res Nerv Ment Dis 53:13, 1974. Choi DW, Rothman SM: The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171, 1990. Choi IS: Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 40:433, 1983. Chong JY, Rowland LP, Utiger RD: Hashimoto encephalopathy: Syndrome or myth? Arch Neurol 60:164, 2003. Cooke WT, Smith WT: Neurologic disorders associated with adult coeliac disease. Brain 89:683, 1966.


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Neurology_Adams. Fishman RA: Cell volume, pumps and neurologic function: Brain’s adaptation to osmotic stress. Res Publ Assoc Res Nerv Ment Dis 53:159, 1974. Foley JM, Watson CW, Adams RD: Significance of the electroencephalographic changes in hepatic coma. Trans Am Neurol Assoc 51:161, 1950. Gomcelli YB, Kutku L, Cavdar L, et al: Different clinical manifestations of hyperammonemic encephalopathy. Epilepsy Behav 10:583, 2007. Griggs RC, Sutton JR: Neurologic manifestations of respiratory diseases, in Asbury AK, McKhann GM, McDonald WI (eds): Diseases of the Nervous System, 2nd ed. Philadelphia, Saunders, 1992, pp 1432–1441. Hackett PH, Roach RC: High-altitude illness. N Engl J Med 345:107, 2001. Hadjivassiliou M, Grünewald RA, Chatopadhyay AK, et al: Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 352:1582, 1998.


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Neurology_Adams. Hornbein TF, Townes BD, Schoene RB, et al: The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med 321:1714, 1989. Huttenlocher P, Trauner D: Reye’s syndrome in infancy. Pediatrics 62:84, 1978. Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:549, 2002. Jellinek EH, Kelly RE: Cerebellar syndrome in myxedema. Lancet 2:225, 1960. Johnson GM, Scurletis TD, Carroll NB: A study of sixteen fatal cases of encephalitis-like disease in North Carolina children. N C Med J 24:464, 1963. Jones EA, Basile AS: Does ammonia contribute to increased GABAergic neurotransmission in liver failure? Metab Brain Dis 13:351, 1998. Karp BI, Laureno R: Pontine and extrapontine myelinolysis: A neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 72:359, 1993.


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Neurology_Adams. Karp BI, Laureno R: Pontine and extrapontine myelinolysis: A neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore) 72:359, 1993. Krane EJ, Rockoff MA, Wallman JK, Walsdorf HU: Subclinical brain swelling in children during treatment of diabetic ketoacidosis. N Engl J Med 312:1147, 1985. Kreiger D, Kreiger S, Jansen O, et al: Manganese and chronic hepatic encephalopathy. Lancet 346:270, 1995. Lance JW, Adams RD: The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 87:111, 1963. Laureno R: Central pontine myelinolysis following rapid correction of hyponatremia. Ann Neurol 13:232, 1983. Laureno R: Neurologic syndromes accompanying electrolyte disorders, in Goetz CG, Tanner CM, Aminoff MKl (eds): Handbook of Clinical Neurology. Vol 63. Amsterdam, Elsevier, 1993, pp 545–573. Lederman RS, Henry CE: Progressive dialysis encephalopathy. Ann Neurol 4:199, 1978.


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Neurology_Adams. Malouf R, Brust JCM: Hypoglycemia: Causes, neurological manifestations, and outcome. Ann Neurol 17:421, 1985. Marinesco G: Lesions en myxoedeme congenitale avec idiotie. Encephale 19:265, 1924. Marshall JR: Neuropsychiatric aspects of renal failure. J Clin Psychiatry 40:181, 1979. McDermott W, Adams RD: Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia. J Clin Invest 33:1, 1954. McKee AC, Winkelman MD, Banker BQ: Central pontine myelinolysis in severely burned patients: Relationship to serum hyperosmolality. Neurology 38:1211, 1988. Merritt HH, Fremont-Smith F: The Cerebrospinal Fluid. Philadelphia, WB Saunders, 1938, p 212. Momose KJ, Kjellberg RN, Kliman B: High incidence of cortical atrophy of the cerebral and cerebellar hemisphere in Cushing’s disease. Radiology 99:341, 1971.


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Neurology_Adams. Momose KJ, Kjellberg RN, Kliman B: High incidence of cortical atrophy of the cerebral and cerebellar hemisphere in Cushing’s disease. Radiology 99:341, 1971. Morgan MY, Jakobovits AW, James IM, Sherlock S: Successful use of bromocriptine in the treatment of chronic hepatic encephalopathy. Gastroenterology 78:663, 1980. Mullen KD: Benzodiazepine compounds and hepatic encephalopathy. N Engl J Med 325:509, 1991. Myers RAM, Snyder SK, Emhoff TA: Subacute sequelae of carbon monoxide poisoning. Ann Emerg Med 14:1163, 1985. Naylor CD, O’Rourke K, Detsky AS, Baker JP: Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy: A meta-analysis. Gastroenterology 97:1033, 1989. Nelson PB, Seif SM, Maroon JC, Robinson AG: Hyponatremia in intracranial disease: Perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg 55:938, 1981. Newcomer J, Haire W, Hartman CR: Coma and thyrotoxicosis. Ann Neurol 14:689, 1983.


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Neurology_Adams. Newcomer J, Haire W, Hartman CR: Coma and thyrotoxicosis. Ann Neurol 14:689, 1983. Nielsen N, Wetterslev J, Cronberg T, et al: Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 369:2197, 2013. Norenberg MD: Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis 13:319, 1998. Oppenheimer BS, Fishberg AM: Hypertensive encephalopathy. Arch Intern Med 41:264, 1928. Pallis CA, Lewis PD: The Neurology of Gastrointestinal Disease. London, Saunders, 1974. Pant SS, Rebeiz J, Richardson EP: Spastic paraparesis following portacaval shunt. Neurology 18:134, 1968. Parkinson IS, Ward MK, Kerr DNS: Dialysis encephalopathy, bone disease and anemia: The aluminum intoxication syndrome during regular hemodialysis. J Clin Pathol 34:1285, 1981. Perrot X, Firaud P, Biacabe A-G, et al: Encephalopathie d’Hashimoto: Une observation anatomo-clinique. Rev Neurol 158:461, 2002.


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Neurology_Adams. Perrot X, Firaud P, Biacabe A-G, et al: Encephalopathie d’Hashimoto: Une observation anatomo-clinique. Rev Neurol 158:461, 2002. Plum F, Posner JB, Hain RF: Delayed neurological deterioration after anoxia. Arch Intern Med 110:18, 1962. Pomier-Layrargues G, Rose C, Spahr L, et al: Role of manganese in the pathogenesis of portal-systemic encephalopathy. Metab Brain Dis 13:311, 1998. Price TR, Netsky MG: Myxedema and ataxia: Cerebellar alterations and “neural myxedema bodies.” Neurology 16:957, 1966. Prockop LD: Hyperglycemia: Effects on the nervous system, in Vinken PJ, Bruyn BW (eds): Handbook of Clinical Neurology. Vol 27: Metabolic and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 79–99. Raskin NH, Fishman RA: Neurologic disorders in renal failure. N Engl J Med 294:143, 204, 1976. Reye RDK, Morgan G, Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 2:749, 1963.


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Neurology_Adams. Reye RDK, Morgan G, Baral J: Encephalopathy and fatty degeneration of the viscera: A disease entity in childhood. Lancet 2:749, 1963. Ropper AH, Gress DR, Diringer MN, et al: Hypoxic-ischemic cerebral injury, in Neurological and Neurosurgical Intensive Care, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 260–277. Rothermich NO, von Haam E: Pancreatic encephalopathy. J Clin Endocrinol 1:872, 1941. Rothstein JD, Herlong HF: Neurologic manifestations of hepatic disease. Neurol Clin 7:563, 1989. Schenone AL, Cohen A, Patarroyo G, et al: Therapeutic hypothermia after cardiac arrest: A systematic review/meta-analysis exploring the impact of expanded criteria and targeted temperature. Resuscitation 108:102, 2016. Schoch HJ, Fischer S, Marti HH: Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125:2549, 2002.


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Neurology_Adams. Schoch HJ, Fischer S, Marti HH: Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain 125:2549, 2002. Sharf B, Levy N: Pancreatic encephalopathy, in Vinken PJ, Bruyn GW, Klawans H (eds): Handbook of Clinical Neurology. Vol 27: Metabolic and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 449–458. Shaw PJ, Walls TJ, Neman MB, et al: Hashimoto’s encephalopathy: A steroid-responsive disorder associated with high anti-thyroid antibody titers—report of 5 cases. Neurology 41:228, 1991. Shaywitz BA, Rothstein P, Venes JL: Monitoring and management of increased intracranial pressure in Reye syndrome: Results in 29 children. Pediatrics 66:198, 1980. Sterns RH, Riggs JE, Schochet SS: Osmotic demyelination syndromes following correction of hyponatremia. N Engl J Med 314:1535, 1986.


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Neurology_Adams. Sterns RH, Riggs JE, Schochet SS: Osmotic demyelination syndromes following correction of hyponatremia. N Engl J Med 314:1535, 1986. Summerskill WHJ, Davidson EA, Sherlock S, Steiner RE: The neuropsychiatric syndrome associated with hepatic cirrhosis and extensive portal collateral circulation. Q J Med 25:245, 1956. Thilly CH, Bourdoux PP, Due DT, et al: Myxedematous cretinism: An indicator of the most severe goiter endemias, in Medeiros-Neto G, Gaitan E (eds): Frontiers in Thyroidology. New York, Plenum Press, 1986, pp 1081–1084. Thomas PK, King RH, Feng SF, et al: Neurological manifestations in chronic mountain sickness: The burning feet–burning hands syndrome. J Neurol Neurosurg Psychiatry 69:447, 2000. Trauner DA: Treatment of Reye syndrome. Ann Neurol 7:2, 1980. van Woerkom W: La cirrhose hepatique avec alterations dans les centres nerveux evoluant chez des sujets d’age moyen. Nouv Iconogr Salpétrière 27:41, 1914.


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Neurology_Adams. van Woerkom W: La cirrhose hepatique avec alterations dans les centres nerveux evoluant chez des sujets d’age moyen. Nouv Iconogr Salpétrière 27:41, 1914. Vassart G, Dumont JE, Refetoff S: Thyroid disorders, in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Diseases, 7th ed. New York, McGraw-Hill, 1995, pp 2883–2928. Victor M, Adams RD, Cole M: The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration. Medicine (Baltimore) 44:345, 1965. Victor M, Laureno R: Neurologic complications of alcohol abuse: Epidemiologic aspects, in Schoenberg BS (ed): Advances in Neurology. Vol 19. New York, Raven Press, 1978, pp 603–617. Volhard F: Clinical aspects of Bright’s disease, in Berglund H, Medes G, Huber CG, et al (eds): The Kidney in Health and Disease. Philadelphia, Lea & Febiger, 1935, pp 665–673.


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Neurology_Adams. Volhard F: Clinical aspects of Bright’s disease, in Berglund H, Medes G, Huber CG, et al (eds): The Kidney in Health and Disease. Philadelphia, Lea & Febiger, 1935, pp 665–673. von Hosslin C, Alzheimer A: Ein Beitrag zur Klinik und pathologischen Anatomie der Westphal-Strumpellschen Pseudosklerose. Z Gesamte Neurol Psychiatr 8:183, 1912. Weaver LK: Carbon monoxide poisoning. N Engl J Med 360:1217, 2009. Weaver LK, Hopkins RO, Chan KJ, et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 347:1057, 2002. Wegierko J: Typical syndrome of clinical manifestations in diabetes mellitus with fatal termination in coma without ketotic acidemia: So-called third coma. Pol Tyg Lek (Wars) 11:2020, 1956. Weiner WJ, Klawans HL: Hyperthyroid chorea, in Vinken PJ, Bruyn BW (eds): Handbook of Clinical Neurology. Vol 27: Metabolic and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 279–281.


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Neurology_Adams. Wijdicks EFM, Plevak DJ, Rakela J, Wiesner RH: Clinical and radiologic features of cerebral edema in fulminant hepatic failure. Mayo Clin Proc 70:119, 1995. Wilkinson DS, Prockop LD: Hypoglycemia: Effects on the nervous system, in Vinken PJ, Bruyn BW (eds): Handbook of Clinical Neurology. Vol 27: Metabolic and Deficiency Diseases of the Nervous System. Part I. Amsterdam, North-Holland, 1976, pp 53–78. Wilson SAK: Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 34:295, 1912. Winkelman MD, Ricanati ES: Dialysis encephalopathy: Neuropathologic aspects. Hum Pathol 17:823, 1986. Wright DG, Laureno R, Victor M: Pontine and extrapontine myelinolysis. Brain 102:361, 1979. Young E, Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. N Engl J Med 276:665, 1967. Zieve L: Pathogenesis of hepatic encephalopathy. Metab Brain Dis 2:147, 1987.


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Neurology_Adams. Young E, Bradley RF: Cerebral edema with irreversible coma in severe diabetic ketoacidosis. N Engl J Med 276:665, 1967. Zieve L: Pathogenesis of hepatic encephalopathy. Metab Brain Dis 2:147, 1987. Figure 39-1. Axial CT without contrast 1 day after cardiac arrest demonstrating loss of distinction between gray and white matter structures throughout the cerebral hemispheres. The patient remained comatose and became vegetative. Figure 39-2. Axial CT without contrast showing arterial borderzone infarctions between the middle and posterior cerebral arteries after brief cardiac arrest. The patient had Balint syndrome. Figure 39-3. Axial T2-weighted MRI showing striatal damage after anoxia from suffocation. The pallidum is relatively spared, in contrast to typical cases of carbon monoxide poisoning (see Fig. 39-5).


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Neurology_Adams. Figure 39-4. Axial T2-fluid-attenuated inversion recovery (FLAIR) MRI of delayed postanoxic leukoencephalopathy in a patient who had recovered after drowning and deteriorated 2 weeks later. Figure 39-5. Axial CT without contrast of a 30-year-old woman who attempted suicide by carbon monoxide inhalation. Small areas of decreased attenuation are seen in the pallidum bilaterally (arrows). The only neurologic residua were a mild defect in retentive memory. Figure 39-6. T2-weighted MRI showing the typical lesion of central pontine myelinolysis in an alcoholic patient. Chapter 39 The Acquired Metabolic Disorders of the Nervous System Diseases of the Nervous System


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Neurology_Adams. Among nutritional disorders, those of the nervous system occupy a position of special interest and importance. The early studies of beriberi at the turn of the 20th century were largely responsible for the discovery of thiamine and consequently for the modern concept of diseases of nutritional deficiency. A series of notable achievements in the science of nutrition followed the discovery of vitamins. Despite such progress, diseases caused by nutritional deficiency, and particularly those of the nervous system, continue to represent a worldwide health problem of serious proportions. In communities where the diet consists mainly of highly milled rice there is still a significant incidence of beriberi. In some developing countries, deficiency diseases are endemic, the result of chronic dietary deprivation. And the ultimate effects on the nervous system of intermittent mass starvation, involving large portions of the African continent, remain an alarming medical and humanitarian crisis.


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Neurology_Adams. In addition to the occurrence in the developing world, it must be acknowledged that diseases of nutritional deficiency are not uncommon in the United States and other parts of the developed world. In addition to deprivation from poverty, other clinical circumstances in which nutritional deficiency can arise are alcoholism, dietary faddism, impaired absorption of dietary nutrients that occurs in conditions such as celiac sprue and pernicious anemia, and the wasting syndromes of cancer and HIV. In the United States, surgical excision of portions of the gastrointestinal tract for treatment of obesity has emerged has an important cause of nutritional deficiency. Finally, there are iatrogenic deficiencies induced by the use of vitamin antagonists or certain drugs, such as methotrexate or isonicotinic acid hydrazide (INH), which interferes with the enzymatic function of pyridoxine.


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Neurology_Adams. The term deficiency is used throughout this chapter in its strictest sense to designate disorders that result from the lack of an essential nutrient or nutrients in the diet or from a conditioning factor that increases the need for these nutrients. The most important of these are the vitamins, especially members of the B group—thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and cobalamin (B12). While some disorders can be attributed to a single vitamin deficiency, such as thiamine deficiency causing Wernicke disease and vitamin B12 deficiency causing subacute combined degeneration [SCD] of the spinal cord, other disorders are the result of multiple nutritional deficiencies. Characteristic of the nutritional diseases is the potential for involvement of both the central and peripheral nervous systems, an attribute shared only with certain metabolic disorders.


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Neurology_Adams. In many cases, vitamin deprivation occurs in the context of general undernutrition, and multisystem effects such as circulatory abnormalities and loss of subcutaneous fat and muscle bulk are usually associated. A total lack of vitamins, therefore, as occurs in starvation, is rarely associated with the classic deficiency syndromes of beriberi or pellagra. In other words, a certain amount of food is necessary to produce the disorders associated with a single vitamin deficiency. In a similar way, excessive intake of carbohydrates relative to the supply of thiamine favors the development of a thiamine-deficiency state. All deficiency diseases, including those of the nervous system, are influenced by factors such as exercise, growth, pregnancy, neoplasia, and systemic infection, which increase the need for essential nutrients, and by disorders of the liver and the gastrointestinal tract, which may interfere with the synthesis and absorption of these nutrients.


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Neurology_Adams. As already mentioned, alcoholism is an important factor in the causation of nutritional diseases of the nervous system. Alcohol acts mainly by displacing food in the diet but also by adding carbohydrate calories (alcohol is burned almost entirely as carbohydrates), thus increasing the need for thiamine. There is some evidence as well that alcohol impairs the absorption of thiamine and other vitamins from the gastrointestinal tract. In infants and young children, a reduction in protein and caloric intake (so-called protein-calorie malnutrition) has a devastating effect on body growth. Whether or not protein-calorie malnutrition also hinders the growth of the brain, with consequent effects on intellectual and behavioral development, cannot be answered as readily. The data bearing on this matter are discussed in the last part of this chapter.


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Neurology_Adams. Some comments will also be made in this chapter about the rare hereditary vitamin-responsive diseases. There are several distinctive neurologic disorders in which nutritional deficiency may partly contribute are discussed in other chapters. These include “alcoholic” cerebellar degeneration (Chap. 41) and central pontine and extrapontine myelinolysis (Chap. 39). Deficiencies of trace elements, because of their rarity, are not discussed; only iodine deficiency (cretinism) is of much importance in humans, and it was discussed in Chap. 39 on acquired metabolic diseases. Wernicke disease and the Korsakoff amnesic state are common neurologic disorders that have been recognized since the 1880s. Wernicke disease is characterized by nystagmus, abducens and conjugate gaze palsies, ataxia of gait, and confusion. These symptoms develop acutely or subacutely and usually occur in varying combinations. Wernicke disease is specifically the result of a deficiency of thiamine.


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Neurology_Adams. The Korsakoff amnesic state (Korsakoff psychosis) is a mental disorder in which retentive memory is impaired out of proportion to all other cognitive functions in an otherwise alert and responsive patient. This amnesic disorder, like Wernicke disease, is most often associated with the thiamine deficiency of alcoholism and malnutrition, but it may be a symptom of various other non-nutritional diseases that have their basis in structural lesions of the medial thalami or the hippocampal portions of the temporal lobes, such as infarction in the territory of branches of the posterior cerebral arteries, hippocampal damage after cardiac arrest, third ventricular tumors, and herpes simplex encephalitis. An almost equivalent type of memory disturbance may also follow acute lesions of the basal septal nuclei of the frontal lobe. Transient impairments of retentive memory of the Korsakoff type may be the salient manifestations of temporal lobe epilepsy, concussive head injury, and a transient


Neurology_Adams

Neurology_Adams. septal nuclei of the frontal lobe. Transient impairments of retentive memory of the Korsakoff type may be the salient manifestations of temporal lobe epilepsy, concussive head injury, and a transient global amnesia. The anatomic basis of the Korsakoff amnesic syndrome is described in Chap. 20.


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Neurology_Adams. In the nutritionally deficient patient, Korsakoff amnesia is usually associated with and immediately follows the occurrence of Wernicke disease. For this reason and others elaborated in the following text, the term Wernicke disease or Wernicke encephalopathy is applied to a symptom complex of ophthalmoparesis, nystagmus, ataxia, and an acute apathetic–confusional state. If an enduring defect in learning and memory results, as it often does, the symptom complex is designated as the Wernicke-Korsakoff syndrome.


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Neurology_Adams. It is perhaps in part due to the emphasis in previous editions of this book that alcoholism has been inordinately associated with this disease complex. The disease arises in many other clinical settings. One of Wernicke’s original cases, for example, occurred in a woman with hyperemesis gravidarum and such instances are still found. However, bariatric surgery, cancer chemotherapy, inanition in HIV and from anorexia nervosa, and even in the frailty of older age, in nutritionally susceptible persons, starvation for economic and social reasons all may give rise to thiamine deficiency. Even the elderly and frail who subsist for years on “tea and toast” can acquire the disease. In addition, there are common medical circumstances in which a subclinical thiamine deficiency becomes manifest. Perhaps the most important of these is a carbohydrate load, particularly the administration of intravenous glucose to a malnourished individual; other precipitants are unbalanced intravenous


Neurology_Adams

Neurology_Adams. Perhaps the most important of these is a carbohydrate load, particularly the administration of intravenous glucose to a malnourished individual; other precipitants are unbalanced intravenous hyperalimentation, refeeding syndrome, thyrotoxicosis, and hypomagnesemia.


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Neurology_Adams. Autopsy studies demonstrate that the many cases of Wernicke disease are undiagnosed. As summarized in the review by Sechi and Serra of published series from several countries, there is a discrepancy between the detection of the process in autopsy series, 0.5 to 3 percent, and the prevalence of the clinical diagnosis, 0.04 to 0.13 percent, indicating that approximately three-quarters of cases are not recognized during life.


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Neurology_Adams. Historical note In 1881, Carl Wernicke first described an illness of sudden onset characterized by paralysis of eye movements, ataxia of gait, and mental confusion. His observations were made in 3 patients, of whom 2 had alcohol dependency and malnutrition and 1 was a young woman with persistent vomiting following the ingestion of sulfuric acid. In each of these patients there was progressive stupor and coma culminating in death. The pathologic changes described by Wernicke consisted of punctate hemorrhages affecting the gray matter around the third and fourth ventricles and aqueduct of Sylvius; he considered these changes to be inflammatory in nature and confined to the gray matter, hence his designation “polioencephalitis hemorrhagica superioris.” In the belief that Gâyet had described an identical disorder in 1875, the term Gâyet-Wernicke is used frequently by French authors. Such a designation is hardly justified insofar as the clinical signs and pathologic changes in Gâyet’s


Neurology_Adams

Neurology_Adams. an identical disorder in 1875, the term Gâyet-Wernicke is used frequently by French authors. Such a designation is hardly justified insofar as the clinical signs and pathologic changes in Gâyet’s patients differed from those of Wernicke’s patients in all essential details.


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Neurology_Adams. The first comprehensive account of this disorder was given by the Russian psychiatrist S.S. Korsakoff in a series of articles published between 1887 and 1891 (for English translation and commentary, see reference by Victor and Yakovlev). Korsakoff stressed the relationship between “neuritis” (a term used at that time for all types of peripheral nerve disease) and the disorder of memory seen in patients with alcoholism, which he believed to be “2 facets of the same disease” and which he called “psychosis polyneuritica.” But he also made the points that neuritis need not accompany the amnesic syndrome and that both disorders could affect nonalcoholic as well as alcoholic patients. His clinical descriptions were remarkably complete and have not been surpassed to the present day. It is of interest that the relationship between Wernicke disease and Korsakoff polyneuritic psychosis was appreciated neither by Wernicke nor by Korsakoff. It was Murawieff, in 1897, who first postulated that a


Neurology_Adams

Neurology_Adams. that the relationship between Wernicke disease and Korsakoff polyneuritic psychosis was appreciated neither by Wernicke nor by Korsakoff. It was Murawieff, in 1897, who first postulated that a single cause was responsible for both. The intimate clinical relationship was established by Bonhoeffer in 1904, who stated that in all cases of Wernicke disease he found neuritis and an amnesic psychosis. Confirmation of this relationship on pathologic grounds came much later. For further details the reader is referred to the extensive monograph by Victor et al (1989).


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Neurology_Adams. The incidence of the Wernicke-Korsakoff syndrome cannot be stated with precision, but it had been a common disorder as noted in the introductory comments. At the Cleveland Metropolitan General Hospital, for example, in a consecutive series of 3,548 autopsies in adults (for the period 1963 to 1976), our colleague M. Victor (1990) found the pathognomonic lesions in 77 cases (2.2 percent). The disease affects males slightly more often than females and the age of onset is fairly evenly distributed between 30 and 70 years. In the past few decades, the incidence of the Wernicke-Korsakoff syndrome has fallen in the alcoholic population, but it is being recognized with increasing frequency among nonalcoholic patients in a variety of clinical settings that are prone to include malnutrition, including iatrogenic ones.


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Neurology_Adams. The triad of clinical features described by Wernicke of ophthalmoplegia (with nystagmus), ataxia, and disturbances of mentation and consciousness is still clinically useful provided that the signs are carefully sought, and one recognizes that all features will not be present. The disease may begin with ataxia, followed in a few days or weeks by mental confusion, or there may be confusion alone, or the more or less simultaneous onset of ataxia, nystagmus, and ophthalmoparesis with or without confusion. In approximately one-third of cases, one component of this triad may be the sole manifestation of the disease. Timely treatment with thiamine can prevent the permanent


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Neurology_Adams. Korsakoff-amnesic component of the disease. A schematic representation of the various features is shown in Fig. 40-1, adapted from the series of 131 autopsied proved cases described by Harper et al. The notable aspects are that all 3 of the typical signs were present in only 16 percent; 1 sign in 31 percent, usually confusion alone; 2 signs in 28 percent; and no signs reported or detected during life in 19 percent. A description of each of the major manifestations follows. Eye movement abnormalities The diagnosis of Wernicke disease is made most readily on the basis of the ocular signs. These consist of (1) nystagmus that is both horizontal and vertical and mainly gaze-evoked, (2) weakness or paralysis of the lateral rectus muscles, and (3) weakness or paralysis of conjugate gaze. Usually there is some combination of these abnormalities (see Chap. 13).


Neurology_Adams

Neurology_Adams. Nystagmus is the most frequent eye movement abnormality seen in Wernicke’s disease, followed in frequency by lateral rectus weakness, which is bilateral but not necessarily symmetrical. With complete paralysis of the lateral rectus muscles, nystagmus is absent in the abducting eyes and it becomes evident as the weakness improves under treatment. The palsy of conjugate gaze varies from merely a paretic nystagmus on extreme gaze to a complete loss of ocular movement in horizontal or vertical movements. Horizonal conjugate gaze palsy is more common than vertical gaze palsy, and isolated paralysis of downward gaze is a known but unusual manifestation. A pattern that simulates internuclear ophthalmoplegia has also been seen. In advanced stages of the disease there may be a complete loss of ocular movements and the pupils, which are otherwise usually spared, may become miotic and nonreacting. Ptosis, small retinal hemorrhages, involvement of the near–far focusing mechanism, and evidence of


Neurology_Adams

Neurology_Adams. movements and the pupils, which are otherwise usually spared, may become miotic and nonreacting. Ptosis, small retinal hemorrhages, involvement of the near–far focusing mechanism, and evidence of optic neuropathy occur occasionally, but neither we nor our colleagues have observed papilledema that was included in Wernicke’s original description. These ocular signs are highly characteristic of Wernicke disease and disappearance of nystagmus and an improvement in ophthalmoparesis within hours or a day of the administration of thiamine confirms the diagnosis.


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Neurology_Adams. Ataxia In the acute stage of the disease the ataxia of stance and gait may be so severe that the patient cannot stand or walk without support. Lesser degrees are characterized by a wide-based stance and a slow, uncertain, short-stepped gait; the mildest degrees are apparent only in tandem walking. In contrast to the gross disorder of locomotion is a relatively infrequent limb ataxia and of intention tremor; when present, they are more likely to be elicited by heel-to-knee than by finger-to-nose testing. Dysarthric, cerebellar-type scanning speech is present only rarely.


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Neurology_Adams. Disturbances of consciousness and mentation These occur in some form in all but 10 percent of patients who have clinical signs. From Fig. 40-1 it can also be appreciated that when there is only one sign of Wernicke disease, it is usually a confusional state. Several related types of disturbed mentation and consciousness are recognized. By far the most common disturbance is a global confusional state. The next following in frequency is memory loss discussed as follows. The patient is apathetic, inattentive, and indifferent to his surroundings. Spontaneous speech is minimal and many questions are left unanswered, or the patient may suspend conversation and drift off to sleep, although he can be aroused without difficulty. Such questions as are answered betray disorientation in time and place, misidentification of those around him, and an inability to grasp the immediate situation. Many of the patient’s remarks may be irrational and lack consistency from one moment to another. If the


Neurology_Adams

Neurology_Adams. misidentification of those around him, and an inability to grasp the immediate situation. Many of the patient’s remarks may be irrational and lack consistency from one moment to another. If the patient’s interest and attention can be maintained long enough to permit adequate testing, one finds that memory and learning ability are also impaired, in this way blending into the


Neurology_Adams

Neurology_Adams. Korsakoff state. In response to the administration of thiamine, the patient rapidly becomes more alert and attentive and more capable of taking part in mental testing. If, however, the state persists for a longer duration before thiamine is administered, the most prominent lasting abnormality becomes one of retentive memory (Korsakoff-amnesic state). Although drowsiness is a common feature of the Wernicke confusional state, more significant stupor and coma are rare as initial manifestations. If, however, the early signs of the disease are not recognized and the patient remains untreated, a progressive depression of the state of consciousness occurs with stupor, coma, and death in a matter of a week or two, just as occurred in Wernicke’s original cases. Autopsy series of Wernicke disease are heavily weighted with cases of this latter type, often undiagnosed during life (Harper; Torvik et al).


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Neurology_Adams. Some patients are alert and responsive from the time they are first seen and already show the characteristic features of the Korsakoff amnesic state. In a small number of such patients, the amnesic state is the only manifestation of the syndrome, and no ocular or ataxic signs (other than possibly nystagmus) can be discerned.


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Neurology_Adams. The amnesic state As indicated in Chap. 20, the core of the amnesic disorder is a defect in learning (anterograde amnesia) and a loss of past memories (retrograde amnesia). The defect in learning can be remarkably severe. The patient may be incapable, for example, of committing to memory the simplest of facts (such as the examiner’s name, the date, and the time of day) despite countless attempts; the patient can repeat each fact as it is presented, indicating that he understands what is wanted of him and that “registration” is intact, but by the time the third fact is repeated, the first may have been forgotten. However, certain nonverbal learning may take place; for example, with repeated trials, the patient may learn complex tasks such as mirror writing or how to negotiate a maze, despite no recollection of ever having been confronted with these tasks.


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Neurology_Adams. Anterograde amnesia is always coupled with a disturbance of past or remote memory (retrograde amnesia). The latter disorder is usually severe in degree, although not complete, and covers a period that antedates the onset of the illness by up to several years. A few isolated events and information from the past are retained, but these are related without regard for the intervals that separated them or for their proper temporal sequence. Usually the patient “telescopes” events into a brief period of time; sometimes the opposite occurs. This aspect of the memory disorder becomes prominent as the initial confusional stage of the illness subsides.


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Neurology_Adams. It is probably true that memories of the recent past are more severely impaired than those of the remote past (the rule of Ribot); language, computation, knowledge acquired in school, and all habitual actions are preserved. This is not to say that all remote memories are intact. As discussed in Chap. 20, these are not as readily tested as more recent memories, making the two difficult to compare. It is our impression that there are gaps and inaccuracies in memories of the distant past in practically all cases of the Korsakoff amnesic state, and serious impairments in many.


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Neurology_Adams. The cognitive impairment of the Korsakoff patient is not exclusively one of memory loss. Psychologic testing discloses that certain cognitive and perceptual functions that depend little or not at all on retentive memory are also impaired. As a rule, the Korsakoff patient has no insight into his illness and is characteristically apathetic and inert, lacking in spontaneity and initiative, and indifferent to everything and everybody around him. However, the patient has a relatively normal capacity to reason with data immediately before him.


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Neurology_Adams. Confabulation had in the past been considered to be a specific feature of Korsakoff psychosis, but the validity of this view depends largely on how one defines confabulation, and there is no uniformity of opinion on this point. The observations of Victor and his colleagues (1959) do not support the oft-repeated statement that the Korsakoff patient fills the gaps in his memory with confabulation. In the sense that gaps in memory exist and that whatever the patient supplies in place of the correct answers fills these gaps, the statement is incontrovertible. It is hardly explanatory, however. The implication that confabulation is a deliberate attempt to hide the memory defect, out of embarrassment or for other reasons, is incorrect. In fact, the opposite seems to pertain: As the patient improves and becomes more aware of a defect in memory, the tendency to confabulate diminishes. Furthermore, confabulation can be associated with both phases of the Wernicke-


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Neurology_Adams. Korsakoff syndrome: The initial one in which profound general confusion dominates the disease, and the convalescent phase in which the patient recalls fragments of past experience in a distorted fashion. Events that were separated by long intervals are juxtaposed or related out of sequence, so that the narrative has an implausible or fictional aspect. In the chronic state of the disease, confabulation is usually absent. These and other aspects of confabulation are discussed fully in the monograph by Victor and colleagues (1959). Other clinical abnormalities Approximately 15 percent of patients show signs of alcohol withdrawal—that is, hallucinations and other disorders of perception, confusion, agitation, tremor, and overactivity of autonomic nervous system function. These symptoms are evanescent in nature and usually mild.


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Neurology_Adams. As Korsakoff pointed out, signs of peripheral neuropathy are common, found in more than 80 percent of patients with the Wernicke-Korsakoff syndrome. In most, the neuropathic disease is mild and does not account for the disorder of gait, but in some it may be severe and particularly painful. In a small number, retrobulbar optic neuropathy is added. Despite the frequency of peripheral neuropathy, overt signs of beriberi heart disease are rare. However, indications of disordered cardiovascular function such as tachycardia, exertional dyspnea, postural hypotension, and minor electrocardiographic abnormalities are frequent; occasionally, the patient dies suddenly following only slight exertion. These patients may show an elevation of cardiac output associated with low peripheral vascular resistance, abnormalities that revert to normal after the administration of thiamine. Postural hypotension and syncope are common findings in Wernicke disease and are probably a result of impaired function


Neurology_Adams

Neurology_Adams. abnormalities that revert to normal after the administration of thiamine. Postural hypotension and syncope are common findings in Wernicke disease and are probably a result of impaired function of the autonomic nervous system, more specifically to a defect in the sympathetic outflow (Birchfield). There may be mild hypothermia, loss of libido, and erectile dysfunction.


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Neurology_Adams. Patients with the Korsakoff amnesic state may have demonstrably impaired olfactory discrimination. This deficit, like the notable apathy present in most Wernicke’s patients, is probably attributable to a lesion of the mediodorsal nucleus of the thalamus and its connections, and not to a lesion of the peripheral olfactory system (Mair et al). Vestibular function, as measured by the response to standard ice-water caloric tests, is universally impaired in the acute stage of Wernicke disease (Ghez), but vertigo is not a complaint. This vestibular paresis probably accounts for the severe disequilibrium in the initial stage of the illness.


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Neurology_Adams. The acute lesions of the Wernicke-Korsakoff syndrome in the mammillary bodies, and other medial thalamic and periaqueductal areas can be demonstrated in most cases by magnetic resonance imaging (MRI) (Donnal et al; Varnet et al). The changes are most apparent on the fluid-attenuated inversion recovery (FLAIR), T2, and diffusion-weighted sequences (if there is necrosis), but they may also enhance as shown in Fig. 40-2. It is not clear to what extent gradient-echo MRI images can be expected to consistently reveal the small hemorrhagic lesions of the diencephalon and periventricular areas. Imaging is particularly useful in patients in whom stupor or coma has supervened or in whom ocular and ataxic signs are otherwise inevident (Victor, 1990), but in milder cases a normal MRI does not preclude the diagnosis. The typical MRI changes are observed in only 58 percent of cases according to Weidauer and colleagues. In the chronic state, the mammillary bodies may be shrunken if measured by


Neurology_Adams

Neurology_Adams. the diagnosis. The typical MRI changes are observed in only 58 percent of cases according to Weidauer and colleagues. In the chronic state, the mammillary bodies may be shrunken if measured by volumetric techniques (Charness and DeLaPaz).


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Neurology_Adams. The cerebrospinal fluid (CSF) in uncomplicated cases of the Wernicke-Korsakoff syndrome is normal or shows only a modest elevation of the protein content. Protein values greater than 100 mg/dL or a pleocytosis indicates the presence of a complicating illness such as subdural hematoma, meningeal infection, or encephalitis. Measurements of serum thiamine and red blood cell transketolase have been explored as aids to diagnosis but are not sufficiently sensitive for clinical use and they are not readily available. Before treatment with thiamine, patients with Wernicke disease show a marked reduction in functional transketolase activity. Restoration of these values and of thiamine diand triphosphate toward normal occurs within a few hours of the administration of thiamine, and completely normal values are usually attained within 24 h.


Neurology_Adams

Neurology_Adams. There are suggestions that there is a hereditary factor in the susceptibility of Wernicke-Korsakoff disease and possibly explains why only a small proportion of nutritionally deficient alcoholic patients develop this disease. Candidates for this variability have been proposed to be in transketolase activity or in the thiamine transporter gene, possibly on an epigenetic basis, but other genetic regions have been studied and no consistent genetic associations have emerged. Approximately half of patients with Wernicke-


Neurology_Adams

Neurology_Adams. Approximately half of patients with Wernicke- Korsakoff disease show electroencephalographic (EEG) abnormalities, consisting of diffuse mild to moderate slow activity. Total cerebral blood flow and cerebral oxygen and glucose consumption may be reduced in the acute stages of the disease and may still be present after several weeks of treatment (Shimojyo et al). These observations indicate that significant reductions in brain metabolism need not be reflected in EEG abnormalities or in depression of the state of consciousness and that the latter is more a function of the location of the lesion than of the overall degree of metabolic defect. Course of the Illness


Neurology_Adams

Neurology_Adams. Course of the Illness The mortality rate in the acute phase of Wernicke disease was 17 percent in the series of patients collected by Victor et al (1989) many decades ago. The fatalities were attributable mainly to hepatic failure and infection (pneumonia, pulmonary tuberculosis, and septicemia being at that time the most common). Some deaths were undoubtedly a result of the cerebral or cardiac effects of thiamine deficiency that had reached an irreversible stage.


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Neurology_Adams. Most patients respond in a fairly predictable manner to the administration of thiamine, as detailed further on. The most dramatic improvement is in the ocular manifestations. Recovery often begins within hours or sooner after the administration of thiamine and practically always within several days. This effect is so constant that a failure of the nystagmus and ocular palsies to respond to thiamine should raise doubts about the diagnosis of Wernicke disease. Horizontal nystagmus sometimes disappears in minutes. Sixth-nerve palsies, ptosis, and vertical gaze palsies recover completely within a week or two in most cases, but vertical nystagmus may sometimes persist for several months. Horizontal gaze palsies usually recover completely, but in 60 percent of cases a fine horizontal nystagmus remains as a permanent sequela. In this respect, horizontal nystagmus is unique among the ocular signs.


Neurology_Adams

Neurology_Adams. In comparison with the ocular signs, improvement of ataxia is delayed. Approximately 40 percent of patients recover completely from ataxia. The remaining patients recover incompletely or not at all and are left with a slow, shuffling, wide-based gait and inability to walk tandem. The residual gait disturbances and horizontal nystagmus provide a means of identifying obscure and chronic cases of dementia as alcoholic-nutritional in origin. Vestibular function improves at about the same rate as the ataxia of gait, and recovery is usually but not always complete. The early symptoms of apathy, drowsiness, and global confusion invariably recede, and as they do the defect in memory and learning stands out more clearly. However, the memory disorder, once established, recovers completely or almost completely in only 20 percent of patients. The remainder is left with varying degrees of permanent Korsakoff amnesia. It is apparent from the foregoing account that


Neurology_Adams

Neurology_Adams. Wernicke disease and Korsakoff amnesia are not separate diseases, but that the ocular and ataxic signs and the transformation of the global confusional state into an amnesic syndrome are successive stages in a single disease process. In the series of Victor et al (1989), of 186 patients who survived the acute illness, 157 (84 percent) showed this sequence of clinical events. As a corollary, a survey of alcoholic patients with Korsakoff amnesia in a psychiatric hospital disclosed that in most patients the illness had begun with the symptoms of Wernicke disease and that approximately 60 percent of them still showed some ocular or cerebellar stigmata of Wernicke disease many years after the onset. The same continuum cannot be invoked to explain alcoholic-nutritional cerebellar degeneration that arises as an independent illness rather than the persistent ataxia of Wernicke disease (see further on and Victor and Adams [1961] and monograph by Victor and Adams).


Neurology_Adams

Neurology_Adams. Patients who die in the acute stages of Wernicke disease show symmetrical lesions in the paraventricular regions of the thalamus and hypothalamus, mammillary bodies, periaqueductal region of the midbrain, floor of the fourth ventricle (particularly in the regions of the dorsal motor nuclei of the vagus and vestibular nuclei), and superior cerebellar vermis. Lesions are consistently found in the mammillary bodies and less consistently in other areas. The microscopic changes are characterized by varying degrees of necrosis of parenchymal structures. Within the area of necrosis, nerve cells are lost, but usually some remain; some of these are damaged but others are intact. Myelinated fibers are more affected than neurons. These changes are accompanied by a prominence of the blood vessels, although in some cases there appears to be a primary endothelial proliferation and evidence of recent or old petechial hemorrhage. In the areas of parenchymal damage there is astrocytic and microglial


Neurology_Adams

Neurology_Adams. in some cases there appears to be a primary endothelial proliferation and evidence of recent or old petechial hemorrhage. In the areas of parenchymal damage there is astrocytic and microglial proliferation. Discrete hemorrhages were found in only 20 percent of Victor’s (1989) cases, and many appeared to be agonal rather than acquired earlier during the acute illness. The cerebellar changes consist of degeneration of all layers of the cortex, particularly of the Purkinje cells; usually this lesion is confined to the superior parts of the vermis, but in advanced cases the most anterior parts of the anterior lobes are involved as well. Of interest is the fact that the lesions of Leigh encephalomyelopathy, a mitochondrial disorder implicating pyruvate metabolism, bear a resemblance to those of Wernicke disease but have a slightly different distribution and histologic characteristics.


Neurology_Adams

Neurology_Adams. The ocular muscle and gaze palsies are attributable to lesions of the sixthand third-nerve nuclei and adjacent tegmentum, and the nystagmus to lesions in the regions of the vestibular nuclei. The latter are also responsible for the loss of caloric responses and probably for the gross disturbance of equilibrium that characterizes the initial stage of the disease. The lack of significant destruction of nerve cells in these lesions accounts for the rapid improvement and the high degree of recovery of oculomotor and vestibular functions. The persistent ataxia of stance and gait is caused by the lesion of the superior vermis of the cerebellum; ataxia of individual movements of the legs is attributable to an extension of the lesion into the anterior parts of the anterior lobes. Hypothermia, which occurs sometimes as an early feature of Wernicke disease, is probably attributable to lesions in the posterior and posterolateral nuclei of the hypothalamus (experimentally placed lesions in these


Neurology_Adams

Neurology_Adams. occurs sometimes as an early feature of Wernicke disease, is probably attributable to lesions in the posterior and posterolateral nuclei of the hypothalamus (experimentally placed lesions in these parts have been shown to cause hypothermia or poikilothermia in monkeys).


Neurology_Adams

Neurology_Adams. The topography of the neuropathologic changes in patients who die in the chronic stages of the disease, when the amnesic symptoms are established, is much the same as the changes in the acute stages of Wernicke disease. Apart from the expected differences in age of the glial and vascular reactions, the only important difference has to do with the involvement of the medial dorsal and anterior nuclei of the thalamus. The medial parts of these nuclei were consistently involved in the patients who had shown the Korsakoff amnesic state during life; they were not affected in patients who had had no persistent amnesic symptoms in the series of Victor et al (1989). The mammillary bodies were affected in all the patients, both those with the amnesic defect and those without. These observations suggest that the lesions responsible for the memory disorder are those of the thalami, predominantly of parts of the medial dorsal nuclei (and their connections with the medial frontal and temporal lobes


Neurology_Adams

Neurology_Adams. that the lesions responsible for the memory disorder are those of the thalami, predominantly of parts of the medial dorsal nuclei (and their connections with the medial frontal and temporal lobes and amygdaloid nuclei), and not those of the mammillary bodies, as is frequently stated. It is notable that the hippocampal formations, the site of damage in most other types of Korsakoff memory loss, are intact.


Neurology_Adams

Neurology_Adams. Treatment of the Wernicke-Korsakoff Syndrome Wernicke disease constitutes a medical emergency; its recognition (or even the suspicion of its presence) requires the administration of thiamine. The prompt use of thiamine prevents progression of the disease and reverses those lesions that have not yet progressed to the point of fixed structural change. As emphasized earlier, in patients who show only ocular signs and ataxia, the administration of thiamine is crucial in preventing the development of an irreversible amnesic state.


Neurology_Adams

Neurology_Adams. Although 2 to 3 mg of thiamine may be sufficient to modify the ocular signs, particularly suppression of nystagmus, much larger doses are needed to sustain improvement and replenish the depleted thiamine stores—initially, 50 to 200 mg intravenously and a similar dose mg intramuscularly—the latter being repeated each day until the patient resumes a normal diet. Certain writings indicate that initial doses of 500 mg are necessary to fully reverse the manifestations of Wernicke disease and prevent progression to the point of a Korsakoff syndrome. It appears that these higher doses, given for several days parenterally, are needed to replete vitamin levels in alcoholic and nutritionally deprived patients (see the articles by Thomson et al and guidelines from the Royal College of Physicians). The risks of administering parenteral thiamine have probably been overstated; anaphylactic reactions occurred in 0.1 percent of the series of Wrenn and colleagues and minor reactions in 1 percent.


Neurology_Adams

Neurology_Adams. To avoid precipitating Wernicke disease, it has become standard practice in emergency departments to administer 100 mg or more of thiamine in malnourished or alcoholic patients if intravenous fluids that contain glucose are being infused. Magnesium is given as well because it is required as cofactor for thiamine activity. It is similarly advisable to give B vitamins to alcoholic patients who are seen for other reasons in the emergency department so as to raise body stores of thiamine and other vitamins. The patient with chronic alcoholism (or the nonalcoholic patient with persistent vomiting) exhausts thiamine in a matter of 7 or 8 weeks, during which time the administration of glucose may serve to precipitate Wernicke disease or cause an early form of the disease to progress rapidly. The further management of Wernicke disease involves the use of a balanced diet and all the B vitamins, as the patient is usually deficient in more than thiamine alone.


Neurology_Adams

Neurology_Adams. A different problem in management may arise once the patient has recovered from Wernicke disease and the amnesic syndrome becomes prominent. Only a minority of such patients (fewer than 20 percent in Victor’s series) recover entirely; moreover, the time of recovery may be delayed for several weeks or even months, and then it proceeds very slowly over a period of many months. The extent to which the amnesic symptoms will recover cannot be predicted during the acute stages of the illness. Interestingly, some patients with alcoholism who develop Korsakoff syndrome, once more or less recovered, seldom demand alcohol but will drink it if it is offered.


Neurology_Adams

Neurology_Adams. This designates an acute and frequently fatal disease of infants, which until recently was common in rice-eating communities of the Far East. It affects only breast-fed infants, usually in the second to the fifth months of life. Acute cardiac symptoms dominate the clinical picture, but neurologic symptoms (aphonia, strabismus, nystagmus, spasmodic contraction of facial muscles, and convulsions) have been described in many of the cases. This syndrome can be reversed dramatically by the administration of thiamine, so that some authors prefer to call it acute thiamine deficiency in infants. In the few neuropathologic studies that are available, changes like those of Wernicke disease in the adult have been described. Occasionally, there are outbreaks of this condition due to inadequately formulated baby foods that lack thiamine.


Neurology_Adams

Neurology_Adams. Infantile beriberi bears no consistent relationship to beriberi in the mother. Infants of mothers with overt signs of beriberi may be quite normal. The absence of beriberi in the mothers of affected infants suggests that infantile beriberi might be due to the result of a toxic factor in breast milk, but such a factor, if it exists, has never been isolated. Rarely, the clinical manifestations of beriberi in infancy represent an inherited (autosomal recessive) thiamine-dependent state, responding to the continued administration of massive doses of thiamine (Mandel et al; see also Table 40-3, further on). NUTRITIONAL POLYNEUROPATHY (NEUROPATHIC BERIBERI) (SEE ALSO CHAP. 43)


Neurology_Adams

Neurology_Adams. NUTRITIONAL POLYNEUROPATHY (NEUROPATHIC BERIBERI) (SEE ALSO CHAP. 43) Beriberi is a distinct clinical entity characterized by a predominantly cardiac disorder occurring among people whose diet is dominated by polished rice. The milling process, or “polishing,” removes the husk that contains most of the vitamin nutrients. In fact, beriberi is not confined to any particular part of the world. In addition to affecting the heart, it also affects the peripheral nerves (which may be affected separately), with or without edema, the latter feature providing the basis for the old division into “wet” and “dry” forms. The cardiac manifestations range from tachycardia and exertional dyspnea to acute and rapidly fatal heart failure, the latter being the most dramatic but uncommon manifestation of beriberi. Here we emphasize the peripheral neuropathy associated with beriberi.


Neurology_Adams

Neurology_Adams. The notion that the neurologic manifestation of beriberi is essentially a peripheral neuropathy was established in the late nineteenth century by the studies of the Dutch investigators Eijkman, Pekelharing and Winkler, and


Neurology_Adams

Neurology_Adams. Grijns. Only after beriberi gained acceptance as a nutritional disease (following Funk’s discovery of vitamins in 1911) was it suspected that the neuropathy of alcoholic patients was also nutritional in origin. The similarity between beriberi and alcoholic neuropathy was commented upon by several authors, but it was Shattuck, in 1928, who first seriously discussed the relationship of the 2 disorders. He suggested that “polyneuritis of chronic alcoholism was caused chiefly by failure to take or assimilate food containing a sufficient quantity B vitamins and might properly be regarded as true beriberi.” Convincing evidence that “alcoholic neuritis” is not a result of the neurotoxic effect of alcohol was supplied by Strauss. He allowed 10 patients to continue their daily consumption of whiskey while they consumed a well-balanced diet supplemented with yeast and vitamin B concentrates; the peripheral nerve symptoms improved in every case. The observations made by Victor (1984) support


Neurology_Adams

Neurology_Adams. while they consumed a well-balanced diet supplemented with yeast and vitamin B concentrates; the peripheral nerve symptoms improved in every case. The observations made by Victor (1984) support Strauss’s contention that alcoholic polyneuropathy is essentially a nutritional disease.


Neurology_Adams

Neurology_Adams. The symptomatology of nutritional polyneuropathy is diverse. In fact, many patients are asymptomatic and evidence of peripheral nerve disease is found only by clinical or electromyographic examination. The mildest neuropathic signs are thinness and tenderness of the leg muscles, loss or depression of the Achilles and perhaps the patellar reflexes, and at times, a patchy blunting of pain and touch sensation over the feet and shins.


Neurology_Adams

Neurology_Adams. Most patients, however, are symptomatic and have weakness, paresthesias, and pain as the usual complaints. The symptoms are insidious in onset and slowly progressive, but occasionally they seem to evolve or to worsen rapidly over a matter of days. The initial symptoms are usually referred to the distal portions of the limbs and progress proximally if the illness remains untreated. The feet are always affected earlier and more severely than the hands. Usually some aspect of motor disability is part of the chief complaint, but in about one-third of the patients the main complaints are pain and paresthesias. It is this painful syndrome that has been the most prominent feature in the patients we have encountered. The discomfort takes several forms: a dull, constant ache in the feet or legs; sharp and lancinating pains, momentary in duration, like those of tabes dorsalis; sensations of cramping or tightness in the muscles of the feet and calves; or band-like feelings around the legs.


Neurology_Adams

Neurology_Adams. sharp and lancinating pains, momentary in duration, like those of tabes dorsalis; sensations of cramping or tightness in the muscles of the feet and calves; or band-like feelings around the legs. Coldness of the feet is a common complaint but is not corroborated by palpation. Far more distressing are feelings of heat or “burning” affecting mainly the soles, less frequently the dorsal aspects of the feet. These dysesthesias fluctuate in severity and characteristically are worsened by contactual stimuli, sometimes to the point where the patient cannot walk or bear the touch of bedclothes, despite the relative preservation of motor power (allodynia). The term burning feet has been applied to this syndrome, but it is not particularly apt, as the patient also complains of other types of paresthesias, dysesthesias, and pain, and these symptoms may involve the hands as well as the feet.


Neurology_Adams

Neurology_Adams. Examination discloses varying degrees of motor, sensory, and reflex loss. As the symptoms suggest, the signs are symmetrical, and more severe in distal than in proximal portions of the limbs, and often confined to the legs. In some cases, the disproportionate affection of motor power may be striking, taking the form of a footand wrist-drop, but the proximal muscles are usually affected as well (indicated, for example, by climbing stairs or by difficulty in arising from a squatting position). In a few patients, the weakness appears to be most severe in the proximal muscles. Absolute paralysis of the legs had been observed in the past only rarely; immobility caused by contractures at the knees and ankles in neglected patients was a more common occurrence. Tenderness of muscles on deep pressure is a highly characteristic finding, elicited most readily in the muscles of the feet and calves. In the arms, tendon reflexes are sometimes retained despite a loss of strength in the hands. In


Neurology_Adams

Neurology_Adams. is a highly characteristic finding, elicited most readily in the muscles of the feet and calves. In the arms, tendon reflexes are sometimes retained despite a loss of strength in the hands. In patients in whom pain and dysesthesias are prominent and motor loss is slight, the reflexes at knee and ankle may be retained or even of greater than average briskness. This attests to the predominant affection of the small nerve fibers.


Neurology_Adams

Neurology_Adams. Excessive sweating of the soles and dorsal aspects of the feet and of the volar surfaces of the hands and fingers is a common manifestation of alcohol-induced nutritional neuropathy. Postural hypotension is also sometimes associated, indicative of involvement of the peripheral sympathetic nerve fibers. Sensory loss or impairment may involve all the modalities, although one may be affected out of proportion to the others, usually pain and temperature. One cannot predict from the patient’s symptoms which mode of sensation might be affected disproportionately. In patients with impairment of superficial sensation (i.e., touch, pain, and temperature), the border between impaired and normal sensation is not sharp but shades off gradually over a considerable vertical extent of the limbs.


Neurology_Adams

Neurology_Adams. Patients in whom pain is the outstanding symptom do not constitute a distinct group in terms of their neurologic signs. Pain and dysesthesias may be prominent in patients with either severe or slight degrees of motor, reflex, and sensory loss. The term hyperesthetic is used commonly to designate the exquisitely painful form of neuropathy but is not well chosen; as pointed out in Chap. 7, one is usually able, by using finely graded stimuli, to demonstrate an elevated threshold to painful, thermal, and tactile stimuli in the “hyperesthetic” zone. Once the stimulus is perceived, however, it has a painful and diffuse, unpleasant quality (hyperpathia). Tactile evocation of pain or burning is an example, as mentioned, of allodynia.


Neurology_Adams

Neurology_Adams. In most patients with nutritional polyneuropathy, only the limbs are involved and the abdominal, thoracic, and bulbar muscles are usually spared; however, we have encountered 2 cases in which there was sensory loss in the pattern of an escutcheon over the anterior thorax and abdomen. In the most advanced instances of neuropathy, hoarseness and weakness of the voice and dysphagia as a result of degeneration of the vagus nerves may be added to the clinical picture.


Neurology_Adams

Neurology_Adams. Some idea of the incidence of the motor, reflex, and sensory abnormalities and the combinations in which they occur can be obtained from Table 40-1, which is based on Victor’s (1984) examination of 189 nutritionally depleted alcoholic patients. Noteworthy is the fact that only 66 (35 percent) of the 189 patients showed the clinical picture of polyneuropathy in its entirety, that is, a symmetrical impairment or loss of tendon reflexes, sensation, and motor power affecting legs more than the arms and the distal more than the proximal segments of the limbs. In the remaining patients, the motor-reflex-sensory signs occurred in various combinations.


Neurology_Adams

Neurology_Adams. Stasis edema and pigmentation, glossiness, and thinness of the skin of the lower legs and feet are common findings in patients with any severe form of neuropathy. Major dystrophic changes, in the form of perforating plantar ulcers and painless destruction of the bones and joints of the feet (“Charcot forefeet”), have been described but are rare. Repeated trauma to insensitive parts and superimposed infection are thought to be responsible for the neuropathic arthropathy, as discussed in Chaps. 7 and 43.


Neurology_Adams

Neurology_Adams. The CSF is usually normal, although a modest elevation of protein content is found in a small number. Findings of nerve conduction studies include mild to moderate degrees of slowing of motor and sensory conduction and a marked reduction in the amplitudes of sensory action potentials; the motor conduction velocities in distal segments of the nerves may be reduced, while conduction in proximal segments is normal. Denervated muscles show fibrillation potentials in a pattern that is consistent with more severe involvement peripherally.


Neurology_Adams

Neurology_Adams. The essential change is one of axonal degeneration, with destruction of both axon and myelin sheath. Segmental demyelination occurs only in a small proportion of fibers. The most pronounced changes are observed in the distal parts of the longest and largest myelinated fibers in the crural and, to a lesser extent, brachial nerves. In advanced cases, the changes extend into the anterior and posterior nerve roots. The vagus and phrenic nerves and paravertebral sympathetic trunks may be affected in advanced cases. Anterior horn and dorsal root ganglion cells undergo chromatolysis, indicating axonal damage. Secondary changes in the posterior columns are seen in some cases.


Neurology_Adams

Neurology_Adams. The nutritional factor(s) responsible for the neuropathy of alcoholism and beriberi has not been defined precisely. Because of the difficulty in producing peripheral neuropathy in mammals by means of a thiamine-deficient diet, the idea that thiamine is the antineuritic vitamin was questioned in the past. Very few of the animal experiments undertaken to settle this point were satisfactory from a nutritional and pathologic point of view. Nevertheless, several studies in birds and humans do indeed indicate that uncomplicated thiamine deficiency may result in peripheral nerve disease. The necessity of either accepting or rejecting the specific role of thiamine became less urgent when it was demonstrated, in both animals and humans; a deficiency of pyridoxine or of pantothenic acid could also result in degeneration of the peripheral nerves and therefore there were alternative reasons for nutritional polyneuropathy (Swank and Adams).


Neurology_Adams

Neurology_Adams. The question of whether polyneuropathy in the alcoholic patient might be a result of the direct toxic effects of alcohol and not of a nutritional deficiency has been raised from time to time (see the preceding text, and Denny-Brown, and Behse and Buchthal). The evidence for this view is not compelling, either on clinical or on experimental grounds, as already mentioned (see reference to Strauss, in introductory section on nutritional neuropathy). The data presented more recently by Koike and colleagues, ostensibly in favor of the existence of a true alcoholic neuropathy, in our view present no convincing support of a direct toxic effect of alcohol. In the end, we view alcoholic–beriberi neuropathy as a multiple B-vitamin deficiency. The interested reader will find a detailed critique of this subject in the chapters by Victor (1970) and by Windebank.


Neurology_Adams

Neurology_Adams. The first consideration is to supply adequate nutrition over a long period in the form of a balanced diet supplemented with B vitamins (equally important is to make certain that the patient follows the prescribed diet). If persistent vomiting or other gastrointestinal complications prevent the patient from eating, parenteral feeding becomes necessary; the vitamins may be given intramuscularly or added to intravenous fluids.


Neurology_Adams

Neurology_Adams. Where pain and sensitivity of the feet are the major complaints, the pressure of bedclothes may be avoided by placing a cradle support over the legs. Aching of the limbs may be related to their immobility, in which case they should be moved passively on frequent occasions. Aspirin or acetaminophen is usually sufficient to control hyperpathia and allodynia; occasionally codeine or methadone must be added. Obviously, opiates and addicting synthetic analgesics should be avoided if possible, but we have resorted to fentanyl patches for short periods in a few severely affected patients. Some of our patients with severe burning pain (similar to causalgia) in the feet had in the past been helped temporarily by blocking the lumbar sympathetic ganglia or by epidural injection of analgesics. The response to phenytoin, carbamazepine, and gabapentin has been inconsistent, but they are widely used. Adrenergic-blocking medication has been of little value and mexiletine, in our experience, of


Neurology_Adams

Neurology_Adams. The response to phenytoin, carbamazepine, and gabapentin has been inconsistent, but they are widely used. Adrenergic-blocking medication has been of little value and mexiletine, in our experience, of uncertain benefit.


Neurology_Adams

Neurology_Adams. The regeneration of peripheral nerves, which may take many months, will be of little avail if the muscles have been allowed to undergo contracture and the joints to become fixed. In cases of severe paralysis, molded splints should be applied to the arms, hands, legs, and feet during periods of rest. Pressure on the heels and elbows can be avoided by padding the splints and by turning the patient frequently or by asking the patient to do so. As function returns, more vigorous physiotherapeutic measures can be undertaken.


Neurology_Adams

Neurology_Adams. Recovery from nutritional polyneuropathy is a slow process. In the mildest cases there may be a considerable restoration of motor function in a few weeks. In severe forms of the disease, many months may pass before the patient is able to walk unaided. The sensory features and pain in particular may be slower to recover, having taken over a year in one of our recently observed patients. The slowness of recovery creates a special problem for the alcoholic patient, in whom the great danger to continued recovery is the resumption of drinking and inadequate diet.


Neurology_Adams

Neurology_Adams. Whether or not riboflavin deficiency leads to neurologic symptoms has been controversial. In the past, there were claims that glossitis, cheilosis, and neuropathy were caused by riboflavin deficiency, but its effects were never isolated. It is a component of general malnutrition, making it difficult to separate the cause of various disorders. Night blindness seems, however, to be caused by B2 deficiency. Antozzi and coworkers reported that a metabolic disorder similar to the Reye syndrome can be caused by riboflavin deficiency and is correctable by administration of riboflavin alone. The affected infants in their studies were hypoglycemic, hypotonic, and episodically weak and unresponsive. Generally, 15 mg per day in divided doses is used for replacement, but restoration of a normal diet is paramount.


Neurology_Adams

Neurology_Adams. Antozzi and colleagues also recorded instances of disease in older children and adults, manifesting as a type of lipid storage polymyopathy as a result of either a deficiency or malabsorption of riboflavin. Presumably, a disorder of flavin metabolism had caused an impairment of both beta-oxidation of fatty acids and respiratory chain I and II complexes. Serum creatine phosphate was normal in these individuals, but carnitine was reduced. The oral administration of 200 mg of riboflavin and 4 g of carnitine per day relieved the symptoms. We have seen one case with a significant recovery after supplementation was instituted. PELLAGRA (NIACIN, NICOTINIC ACID,


Neurology_Adams

Neurology_Adams. PELLAGRA (NIACIN, NICOTINIC ACID, In the early 1900s, pellagra attained epidemic proportions in the southern United States and in the alcoholic population of large urban centers. Since 1940, it has diminished greatly because of the general practice of enriching bread with niacin. Nevertheless, among the vegetarian, maize-eating people of underdeveloped countries, and among the black population of South Africa, pellagra is still a common disease (Bomb et al; Shah et al; Ronthal and Adler). In developed countries, pellagra is practically confined to malnourished alcoholic patients (Ishii and Nishihara; Spivak and Jackson; Serdaru et al).


Neurology_Adams

Neurology_Adams. In its fully developed form, pellagra affects the skin, alimentary tract, and hematopoietic and nervous systems. The early symptoms may be mistaken for those of a psychiatric disorder. Insomnia, fatigue, nervousness, irritability, and feelings of depression are common complaints; taken together they have the character of neurasthenia. Examination discloses mental dullness, apathy, and a mild impairment of memory. Sometimes an acute confusional psychosis dominates the clinical picture. Untreated, these symptoms may progress to a dementia. Pellagra may not only produce mental impairment but occasionally result from it, by virtue of anorexia and refusal of food. The dermatologic feature, often the aspect that permits one to make a confident diagnosis, is a scaly dermatitis in sun-exposed areas, followed by hyperpigmentation of these areas. Diarrhea and glossitis or other forms of mucous membrane disorder may be accompaniments (hence the alliterative triad dementia-dermatitis-diarrhea).


Neurology_Adams

Neurology_Adams. followed by hyperpigmentation of these areas. Diarrhea and glossitis or other forms of mucous membrane disorder may be accompaniments (hence the alliterative triad dementia-dermatitis-diarrhea). The spinal cord manifestations have not been clearly delineated, but in general, the signs are referable to both posterior and lateral columns, predominantly the former, and thereby simulating SCD. Signs of peripheral neuropathy are relatively less common and are indistinguishable from those of neuropathic beriberi.


Neurology_Adams

Neurology_Adams. These are most readily discerned in the large cells of the motor cortex (Betz cells), and to a lesser extent in the smaller pyramidal cells of the cortex, the large cells of the basal ganglia, the cranial motor and cerebellar dentate nuclei, and the anterior horn cells of the spinal cord. The affected neurons are swollen and rounded, with eccentric nuclei and loss of the Nissl bodies that have the appearance of a secondary axonal reaction. However, in the pathologic material presented by Hauw and associates, these chromatolytic changes were most pronounced in the brainstem nuclei (upper reticular and pontine) and not in the Betz cells. They concluded that the neuronal changes were not caused by a retrograde axonal lesion but did not comment on the status of the spinal cord or nerves. The few studies of the peripheral nerves in pellagra have disclosed changes like those in alcoholics and other patients with nutritional deficiency.


Neurology_Adams

Neurology_Adams. The spinal cord lesions in pellagra take the form of a symmetrical degeneration of the dorsal columns, especially of Goll, and to a lesser extent of the corticospinal tracts. The posterior column degeneration is likely to be secondary to degeneration of the dorsal root ganglion cells or posterior roots. The exact mechanisms underlying the corticospinal tract degeneration have not been elucidated. It has been known since 1937, when Elvehjem and coworkers showed that nicotinic acid cured black tongue, a pellagra-like disease in dogs, that this vitamin is effective in the treatment of pellagra. Many years before,