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Hepatic myelopathy Case report with review of the literature
Clinical Neurology and Neurosurgery ELSEVIER
Clinical Neurology and Neurosurgery98 (1996) 242-246
Case report
Hepatic myelopathy Case report with review of the literature Joseph V. Campellone a,*, David Lacomis a,b, Michael J. GiulianP, Frank J. Kroboth ° ~Department of Neurology, The University of Pittsburg Medical Center, 322 Scaife Hall, Pittsburgh, PA 19512, USA bDepartment of Pathology, The University of Pittsburg Medical Center, Pittsburgh, PA, USA CDepartment of Internal Medicine, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Received 29 January 1996; revised 7 March 1996; accepted 7 March 1996
Abstract Hepatic myelopathy is a rare complication of hepatic insufficiency, causing progressive spastic paraparesis. There are few reports detailing the clinical and diagnostic aspects of this uncommon cause of neurological deterioration in patients with liver disease. Early recognition of this disorder will become more important as patients with liver disease survive longer due to medical advances, including liver transplantation. We present an additional patient with hepatic myelopathy associated with infantile portal vein thrombosis and review the previous reports of hepatic myelopathy in the English literature. Keywords: Myelopathy; Porto-caval shunt; Liver disease; Paraparesis
1. Introduction The development of permanent spastic paraparesis in patients with chronic liver disease is rare, but it may have a significant impact on mobility and quality of life. This entity, now recognized as hepatic myelopathy (HM), has been associated with a broad range of liver diseases, especially those involving porto-caval shunting. Since patients with H M now have prolonged survival due to technological advances including liver transplantation, greater understanding and recognition of this rare cause o f morbidity will become even more important. We report a patient with infantile Banti's syndrome, or idiopathic portal hypertension, who developed symptoms and signs typical of H M later in life. The exclusion of other processes with magnetic resonance and viral assays has not been technically feasible until recently, making our patient one of only a few with such an extensive evaluation. Additionally, the long duration of portocaval shunting present in our patient before the onset of neurological complications *Corresponding author. Fax: +1 412 648-1239.
is somewhat unusual and warrants notice. A review of the English literature is presented with the goal of promoting prompt recognition and enhancing understanding of HM.
2. Case report A 35-year-old man with idiopathic portal hypertension and cirrhosis insidiously developed difficulty arising from a chair and climbing stairs. The bilateral leg weakness progressed over several months. During that period, he experienced several episodes of mild encephalopathy, once requiring hospitalization for more severe confusion. Serum ammonia was elevated on several of these occasions, frequently greater than 120 ~tmol/ml (normal= 9-33 ].tmol/ml). He was able to walk short distances but required a wheelchair for extended travel. He complained of stiffness and 'spasms' in his legs. There were no lower extremity paresthesias, upper extremity neurological symptoms, or symptoms related to cranial nerve dysfunction. He denied bowel, bladder, or sexual disturbance. There was no history of alcohol or
0303-8467/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. PII S0303-8467(96)000 1 8-2
J. K Campellone et al. / Clinical Neurology and Neurosurgery 98 (1996) 242-246
Table 1 Summary of the usual demographic,clinical, and laboratory features of hepatic myelopathy Usually porto-systemicshunt Episodes of encephalopathywith hyperammonemia Male predominance Gait disturbance with spastic paraparesis Rare sensory, bowel, or bladder dysfunction Normal spinal imaging Normal B12 levels AceUular cerebrospinal fluid; glutamine and rarely protein may be elevated Corticospinal tract demyelination in caudal greater than cervical spinal segments Non-pyramidal tract pathology is atypical and when present, may be a result of coexisting disease such as alcohol abuse Alzheimer type-II cells commonlypresent in cerebral cortex
illicit drug use nor familial history of spastic paraparesis. His medical history was significant for multiple episodes of upper gastrointestinal bleeding since the age of 18 months, requiring multiple variceal ligations and several blood transfusions. Repeated hemorrhages necessitated distal esophagectomy, partial gastrectomy, ileal interposition, splenectomy, and central splenorenal shunting. Liver biopsy at that time (1988) revealed mostly preserved architecture, but by 1992, imaging studies began to demonstrate evidence of cirrhosis. Seven years before developing the current neurologic symptoms, he had bilateral distal leg weakness and painful paresthesias following a massive variceal hemorrhage, but there was full recovery over the following 6 months. He reported no weakness or limitations of daily activities following recovery from this event and was fully independent and ambulatory before the onset of his present neurologic complaints. He was treated with lactulose, neomycin, and propanolol. Physical examination revealed normal mental status and cranial nerve function, the absence of asterixis, and a mild tremor of the upper extremities. KayserFleischer rings were absent. Upper extremity strength and bulk were normal. Upper extremity tendon reflexes were brisk; there was a. mild spastic catch of the left upper extremity. Hoffman's sign was absent. In the lower extremities, the tone was more noticeably increased with brisk tendon reflexes, including crossed adductor reflexes, and there was clonus at the ankles. Plantar reflexes were extensor. There was no atrophy nor fasciculations. Strength was symmetric, with the hip flexors being Medical Research Council grade 3+/5; hamstrings 4/5; and ankle dorsi-flexors 4-/5. Knee extensors and plantar flexors were normal in strength. Upper extremity sensation was normal, but proprioception and vibration were mildly decreased in the toes; there was hyperesthesia to pinprick in the feet. There was no
243
sensory level on the trunk, and perianal sensation was normal. Gait was markedly spastic. Laboratory evaluation disclosed a normal ANA titer, and erythrocyte sedimentation rate. Two measurements of vitamin B12 were normal. Serum antibodies to Human T-cell lymphotrophic virus (HTLV-1), Human Immunodeficiency virus (HIV-1), and Hepatitis B virus (HBV) were absent. Hepatitis C virus (HCV) antibody assay was positive, but serum testing for HCV D N A via polymerase chain-reaction was negative. Cerebrospinal fluid (CSF) contained normal glucose, protein, and cell counts. Non-enhanced and gadolinium enhanced MRI of the cervical and thoracic spinal cord revealed no abnormalities. Prior MRI of the brain revealed mild generalized atrophy and no evidence of abnormalities in the white matter. There was mildly increased signal in the bilateral putamen, consistent with changes seen in patients with a history of portal-systemic encephalopathy [1]. Abdominal computed tomography (CT) revealed a cirrhotic liver, thrombosis of the portal vein, and extensive collateralization and varices. Portal vein thrombosis and collateralization was also demonstrated on superior mesenteric arteriography. After several weeks of oral lioresal, he had improved mobility, with decreased spasticity but without significant changes in the remainder of his neurological examination.
3. Discussion 3.1. The clinical features and diagnosis o f hepatic myelopathy
Hepatic myelopathy should be diagnosed only after a thorough evaluation for more common causes of spastic paraparesis, mainly those involving compression or expansion of the spinal cord. A completely normal MRI of our patient's spinal cord excluded such etiologies, including epidural cord compression, intrinsic cord tumor, or infarction. Infection with HIV or HTLV-1 and vitamin B12 deficiency were also absent. Hepatic myelopathy must also be differentiated from other neurological complications of liver disease. NonWilsonian hepato-cerebral degeneration is a permanent, progressive degeneration of the nervous system, causing cognitive, cerebellar, pyramidal, and extrapyramidal dysfunction in various combinations [2-4]. Patients with otherwise uncomplicated cases of hepatic encephalopathy may also exhibit transient upper motor neuron signs. [2,4,5]. In these circumstances, distinction from HM may be impossible until the non-pyramidal neurologic abnormalities abate with correction of the metabolic disturbance. Lockwood remarks on the need to distinguish these processes from the entity now distinctly recognized as 'hepatic myelopathy' or 'portal-
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J.V. Campellone et al./ Clinical Neurology and Neurosurgery 98 (1996) 242-246
systemic myelopathy' [2]. There are few reported cases of hepatocerebral degeneration in which permanent corticospinal tract dysfunction is the predominant feature. This complication seems to be much less frequent than other neurologic sequelae from hepatic insufficiency. In one of the largest series of acquired hepatocerebral degeneration, Victor et al. reported no such cases among 27 patients they observed [4]. Our patient had the typical clinical features of HM (see Table 1), namely the insidious progression of spasticity and weakness in the lower extremities. Initially, the symptoms may be slightly asymmetric, but will invariably affect both legs and steadily worsen. Most commonly, symptoms will develop after several bouts of hepatic encephalopathy, although rarely myelopathy may be the presenting manifestation of liver failure. The signs of corticospinal tract damage appear to accumulate with each episode, although other neurologic signs resolve completely. Upper extremities are affected minimally, if at all [6-8]. Increased tone and hyperreflexia are the most prominent findings. Various plantar responses have been described, even in patients with ankle and knee clonus. Most cases involving disturbance of sensation or bladder function occurred in patients with concurrent neuropathy, probably from alcoholism [9-12], although incontinence was a presenting symptom in one patient without peripheral neuropathy [13]. For unknown reasons, men comprise the large majority of reported cases. After months, the process plateaus, leaving most patients either dependent upon an assistive device or confined to a wheelchair. The evaluation of patients with HM reveals no significant abnormality on neuroimaging with vertebral roentgenograms, myelography, or MRI. Lumbar puncture usually reveals no abnormalities other than an elevated glutamine level [14,15], although increased protein content is rarely noted [9,16]. Consistent with the clinical absence of lower motor neuron signs, electromyography is unrevealing [17]. Electroencephalography usually demonstrates diffuse slowing during episodes of encephalopathy, although some slowing may persist despite an apparently normal mental status [14,18].
3.2. The pathogenesis of hepatic myelopathy The first recognition of spinal cord pathology in patients with liver failure is attributed to Leigh and Card, who reported a patient with hepatocerebral degeneration and spastic weakness of the lower extremities [19]. Histopathologic study revealed demyelination in the corticospinal tracts and posterior columns in addition to Alzheimer type-II cells and spongy degeneration in the cerebral cortex. The authors attributed the spinal cord demyelination to nutritional deficiency and the findings in the brain to a deficiency of a hepatic product. The patient previously received radiation treatment
for suspected lymphoma, and the relationship of this treatment to the clinical and pathologic findings in this case is unclear, since the radiation field size and amount were not reported. Systemic shunting of portal blood was first associated with neurologic dysfunction in humans in 1954 when Sherlock and colleagues coined the term 'portal-systemic encephalopathy' in their paper describing diverse neurological symptoms in patients with hepatic disease [5]. They correlated degree of symptomatology with serum ammonia levels and suggested that delivery of nitrogen containing substances into the systemic circulation results in nervous system intoxication. The first accounts of typical HM were reported by Zieve and co-workers, who described patients with extreme sensitivity to dietary protein resulting in repeated episodes of hepatic encephalopathy [9,10]. Coma was associated with elevated ammonia levels which responded to protein restriction and intravenous arginine. With each episode of coma, the patients developed cumulative leg weakness and spasticity, except for one patient who had persistent organic brain dysfunction and alcoholism. Surgical portal-systemic shunts were present in these patients for over two years before symptoms of HM appeared, and the authors implicated the shunting as a possible etiologic factor in the development of the permanent neurological sequelae. The authors could not discount the role of gastrectomy, although two similar patients without gastrectomy were subsequently reported by Pant et al. [20] further implying a relationship between HM and shunting. Following increased recognition of this syndrome and possibly due to improved survival among patients with portal-systemic shunts, more descriptions of pyramidal tract dysfunction in liver failure followed [7,2131]. Many of the earlier cases were associated with significant non-pyramidal neurological signs and would more appropriately be classified as examples of hepatocerebral degeneration [4,5,7,22]. Furthermore, patients with atypical features were found to have Wilson's disease at autopsy [29], or there were confounding disorders such as pontine tumors and thoracic vertebral fractures [12]. Regardless, more current descriptions continue to relate portal-systemic shunting to corticospinal tract pathology. Implicated by early authors and further supported by more recent observations, portocaval shunts [5,7,8,1115,21-27,29-31], or less commonly splenorenal shunts [18,30], appear to have a substantive role in the neurologic deterioration. The portocaval shunts can occur either spontaneously, after surgery, or due to 'functional shunting' [7] -- filtration of portal blood through a non-functioning liver. Our patient had both longstanding portocaval shunting and more recent surgical splenorenal shunting. Although the duration between shunting and onset of neurologic symptoms may vary,
J.V. Campellone et al. I Clinical Neurology and Neurosurgery 98 (1996) 242-246
it commonly takes 6-36 months before patients notice difficulty walking; this delay is somewhat longer in patients with splenorenal shunts. Given the apparent relationship to shunting and improvement with protein restriction, many authors have suggested the spinal cord insult is due to nitrogenous toxins that are inappropriately delivered to the systemic circulation [5,10]. Ammonia is the most frequently implicated agent, although mercaptan and other substances are suitable candidates [10,11,14]. Others have suggested that altered spinal hemodynamics secondary to the effects of shunting may be respor~Lsible [25], although there are few data to support this contention. Selective demyelination of the corticospinal tracts is a universal finding in the pathologic studies of patients with HM. In correlation with the clinical descriptions, demyelination first becomes noticeably evident in the low cervical cord and is more prominent in caudal regions. Although the predominant process is demyelination with secondary reactive changes, axonal loss or distortion are occasionaLlly noted [17,18]. Minor abnormalities in the posterior columns [17], spinothalamic tracts, or spinocerebellar tracts [16] are infrequently reported, and are possibly related to alcohol use [17]. The most common finding in patients with liver disease [3,4], the Alzheimer type-II cell, is frequently present in the cerebral cortices [7,10,15,29] and occasionally more diffusely [18,19,21,25] in HIVl patients, despite the absence of clinical correlates. Observations of decreased numbers of Betz cells [17] were not confirmed by others [10,15,16,18], and the pyramidal tracts were noted to be normal as they pass through the internal capsules and brainstem [17,29]. Perivascular lymphocytic infiltrates, lipid-laden macrophages, and neuronal loss in the spinal gray matter [25] were also noted. Vascular structures in the spinal c,ord are routinely normal. Our patient had mildly increased signal in the putamen, a common finding in patients with liver disease[l]. More patients with HM will require study via brain imaging with pathologic correlation before the relevance of this finding is understood.
3.3. Treatment of hepatic myelopathy In most patients, therapy directed at reducing nitrogen absorption was generally unrewarding. Protein restriction [8,13-15,18,301i, oral neomycin [5,8,10,1315,18,20,23,26,30], lactulose [15,26], and colonic exclusion [15,23] failed to produce significant improvement. At best, these measures prevented or decreased the numbers of encephalopathic episodes [6,29]. Even so, progressive paraparesis 'was observed even when encephalopathy was effectively averted. Symptomatic treatment, consisting of lioresal, has improved our patient's ability to ambulate, altlhough others have found this therapy of no benefit [27]. One patient experienced
245
more noticeable improvement with a carbidopa/levodopa preparation [13], but this observation has not been duplicated. Administration of flumazenil, a benzodiazepine receptor antagonist, has been demonstrated to temporarily benefit the symptoms of hepatic encephalopathy [32], and the effect of this drug on the course of HM warrants study. We could find no reports of liver transplantation among this patient population. As this procedure becomes more widely performed, symptoms heralding the development of HM may be sufficient to warrant urgent transplantation, given the usually debilitating outcome of this process.
References [1] Uchino, A., Hasuo, K., Matsumoto, S., Masuda, K. (1994) Cerebral magnetic resonance imaging of liver cirrhosis patients. Clin. Imaging, 18 (2): 123-130. [2] Lockwood, A.H. (1992) Hepatic encephalopathy. In: A.I Arieff, R.C. Griggs (Eds.), Metabolic Brain Dysfunction in Systemic Disease. Little, Brown and Co., Boston, pp. 167-182. [3] Brown, I.A. (1957) Liver-brain relationship. Charles C. Thomas. Springfield, 198 pp. [4] Victor, M., Adams, R.D. (1965) The acquired type of chronic hepatocerebral degeneration. Medicine, 44: 345-396. [5] Sherlock, S., Summerskill, W.H.J., White, L.P., Phear, E.A. (1954) Portal-systemic encephalopathy: neurological complications of liver disease. Lancet, Sept. 4, 453-457. [6] Scobie, B.A., Summerskill, W.H.J. (1964) Permanent paraplegia with cirrhosis. Arch. Int. Med., 113: 805-810. [7] Baltzan, M.A., Olszewski, J., Zervas, N. (1957) Chronic Portohepatic encephalopathy. J. Neuropathol. Exp. Neurol., 16: 410421. [8] Robinson, C.E., Anzarut, A. (1979) Myelopathy in cirrhosis. Paraplegia, 16: 3-4. [9] Zieve L., Mendelson D.F., Goepfert, M. (1960) Shunt encephalomyelopathy. I. Recurrent protein encephalopathy with response to arginine. Ann. Int. Med., 53: 33-52. [10] Zieve L., Mendelson, D.F., Goepfert, M. (1960) Shunt encephalomyelopathy. II. Occurrence of permanent myelopathy. Ann. Int. Med., 53: 53-63. [11] Bain, V.G., Bailey, R.J., Jhamandas, J.H. (1991) Postshunt myelopathy. J. Clin. Gastroenterol., 13 (5): 562-4. [12] Lebovics, E., DeMatteo, R.E., Schaffner, F., Gendelman, S. (1985) Portal-systemic myelopathy after portacaval shunt surgery. Arch. Int. Med., 145: 1921-1922. [13] Rab, S.M., Abbas Hussain, S.M. (1985) Spastic paraparesis with cirrhosis of the liver. Br. J. Clin. Pract., 39: 244-246. [14] Mousseau, R., Reynolds, T. (1976) Hepatic paraplegia. Am. J. Gastroenterol., 66: 343-348. [15] Bechar, M., Freud, M., Kott, E., Kott, I., Kravvic, H., Stern, J., Sandbank, U., Bornstein, B. (1970) Hepatic cirrhosis with postshunt myelopathy. J. Neurol. Sci., 11: 101-107. [16] Sobukawa, E., Sakimura, K., Hoshino, S., Hoshino, M., Miyoshi, K. (1994) Hepatic myelopathy: an unusual neurological complication of advanced hepatic disease. Int. Med., 33: 718722. [17] Pant, S.S., Rebeiz, J.J., Richardson, E.P. (1968) Spastic paraparesis following portocaval shunts. Neurology, 18: 134-141. [18] Lefer, L.G., Vogel, F.S. (1972) Encephalomyelopathy with hepatic cirrhosis following portosystemic venous shunts. Arch. Path., 93 : 91-97. [19] Leigh, A.D., Card, W.I. (1949) Hepato-lenticular degeneration:
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A case associated with postero-lateral column degeneration. J. Neuropath. Exp. Neurol., 8: 338-346. [20] Pant, S.S., Bhargava, A.N., Singh, M.M., Dhanda, P.C. (1963) Myelopathy in hepatic cirrhosis. Br. Med. J., April 20: 10641065. [21] Witts, L.J. (1962) Clinicopathologic conference. Br. Med. J., 1: 1198-2000. [22] Drake, A., Patterson, M. (1964) Chronic permanent encephalomyelopathy following portal-systemic shunts. Southern Med. J., 57: 617-622. [23] Stables, D.P., Levin, B., Elliott, G.A., DuPlessis, D.L. (1966) Colonic exclusion for chronic portal-systemic encephalomyelopathy. Ann. Int. Med., 65(2): 326-329. [24] Budillon, G., Scala, G., Mansi, D., Campanella, G. (1979) Hepatic paraplegia: An uncommon complication of portosystemic shunt. Acta Neurol. (Napoli), 34: 93-100. [25] Giangaspero, F., Dondi, C., Scarani, P., Zanetti, G., Marchesini, G. (1985) Degeneration of the corticospinal tract following portosystemic shunt associated with spinal cord infarction. Virchows Arch, 406: 475-481. [26] Demirci, M., Tan, E., Elibol, B., Gedikoglu, G., Saribas, O. (1992) Spastic paraparesis associated with portal-systemic shunting due to congenital hepatic fibrosis. Neurology, 42:983 985.
[27] Mendoza, G., Marti-Fabregas, J., Kulisevsky, J., Escartin, A. (1994) Hepatic myelopathy: a rare complication of portacaval shunt. Eur. Neurol., 34: 209-212. [28] Hoyumpa, A.M., Desmond, P.V., Avant, G.R., Roberts, R.K., Schenker, S. (1979) Hepatic encephalopathy. Gastroenterology, 76(1): 184-195. [29] Liversedge, L.A., Rawson, M.D. (1966) Myelopathy in liver disease and portosystemic venous anastomoses. Lancet, Feb 5 : 277279. [30] Read, A.E., Sherlock, S., Laidlaw, J., Walker, J.G. (1967) The neuro-psychiatric syndromes associated with chronic liver disease and an extensive portal-sytemic collateral circulation. Q. J. Med., 141 : 135-150. [31] Krinashwani, V., Radhakrishnan, T., Michael-John, B. (1969) Myelopathy in cirrhosis. J. Ind. Med. Assoc., 53: 195-197. [32] Pomier-Layrargues, G., Giguere, J.F., Lavoie, J., Perney, P., Gagnon, S., D'amour, M., Wells, J., Butterworth, R.F. (1994) Flumazenil in cirrhotic patients in hepatic coma: A randomized Double-blind placebo controlled crossover trial. Hepatology, 19: 32-37.
Clinical Neurology and Neurosurgery98 (1996) 242-246
Case report
Hepatic myelopathy Case report with review of the literature Joseph V. Campellone a,*, David Lacomis a,b, Michael J. GiulianP, Frank J. Kroboth ° ~Department of Neurology, The University of Pittsburg Medical Center, 322 Scaife Hall, Pittsburgh, PA 19512, USA bDepartment of Pathology, The University of Pittsburg Medical Center, Pittsburgh, PA, USA CDepartment of Internal Medicine, The University of Pittsburgh Medical Center, Pittsburgh, PA, USA
Received 29 January 1996; revised 7 March 1996; accepted 7 March 1996
Abstract Hepatic myelopathy is a rare complication of hepatic insufficiency, causing progressive spastic paraparesis. There are few reports detailing the clinical and diagnostic aspects of this uncommon cause of neurological deterioration in patients with liver disease. Early recognition of this disorder will become more important as patients with liver disease survive longer due to medical advances, including liver transplantation. We present an additional patient with hepatic myelopathy associated with infantile portal vein thrombosis and review the previous reports of hepatic myelopathy in the English literature. Keywords: Myelopathy; Porto-caval shunt; Liver disease; Paraparesis
1. Introduction The development of permanent spastic paraparesis in patients with chronic liver disease is rare, but it may have a significant impact on mobility and quality of life. This entity, now recognized as hepatic myelopathy (HM), has been associated with a broad range of liver diseases, especially those involving porto-caval shunting. Since patients with H M now have prolonged survival due to technological advances including liver transplantation, greater understanding and recognition of this rare cause o f morbidity will become even more important. We report a patient with infantile Banti's syndrome, or idiopathic portal hypertension, who developed symptoms and signs typical of H M later in life. The exclusion of other processes with magnetic resonance and viral assays has not been technically feasible until recently, making our patient one of only a few with such an extensive evaluation. Additionally, the long duration of portocaval shunting present in our patient before the onset of neurological complications *Corresponding author. Fax: +1 412 648-1239.
is somewhat unusual and warrants notice. A review of the English literature is presented with the goal of promoting prompt recognition and enhancing understanding of HM.
2. Case report A 35-year-old man with idiopathic portal hypertension and cirrhosis insidiously developed difficulty arising from a chair and climbing stairs. The bilateral leg weakness progressed over several months. During that period, he experienced several episodes of mild encephalopathy, once requiring hospitalization for more severe confusion. Serum ammonia was elevated on several of these occasions, frequently greater than 120 ~tmol/ml (normal= 9-33 ].tmol/ml). He was able to walk short distances but required a wheelchair for extended travel. He complained of stiffness and 'spasms' in his legs. There were no lower extremity paresthesias, upper extremity neurological symptoms, or symptoms related to cranial nerve dysfunction. He denied bowel, bladder, or sexual disturbance. There was no history of alcohol or
0303-8467/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. PII S0303-8467(96)000 1 8-2
J. K Campellone et al. / Clinical Neurology and Neurosurgery 98 (1996) 242-246
Table 1 Summary of the usual demographic,clinical, and laboratory features of hepatic myelopathy Usually porto-systemicshunt Episodes of encephalopathywith hyperammonemia Male predominance Gait disturbance with spastic paraparesis Rare sensory, bowel, or bladder dysfunction Normal spinal imaging Normal B12 levels AceUular cerebrospinal fluid; glutamine and rarely protein may be elevated Corticospinal tract demyelination in caudal greater than cervical spinal segments Non-pyramidal tract pathology is atypical and when present, may be a result of coexisting disease such as alcohol abuse Alzheimer type-II cells commonlypresent in cerebral cortex
illicit drug use nor familial history of spastic paraparesis. His medical history was significant for multiple episodes of upper gastrointestinal bleeding since the age of 18 months, requiring multiple variceal ligations and several blood transfusions. Repeated hemorrhages necessitated distal esophagectomy, partial gastrectomy, ileal interposition, splenectomy, and central splenorenal shunting. Liver biopsy at that time (1988) revealed mostly preserved architecture, but by 1992, imaging studies began to demonstrate evidence of cirrhosis. Seven years before developing the current neurologic symptoms, he had bilateral distal leg weakness and painful paresthesias following a massive variceal hemorrhage, but there was full recovery over the following 6 months. He reported no weakness or limitations of daily activities following recovery from this event and was fully independent and ambulatory before the onset of his present neurologic complaints. He was treated with lactulose, neomycin, and propanolol. Physical examination revealed normal mental status and cranial nerve function, the absence of asterixis, and a mild tremor of the upper extremities. KayserFleischer rings were absent. Upper extremity strength and bulk were normal. Upper extremity tendon reflexes were brisk; there was a. mild spastic catch of the left upper extremity. Hoffman's sign was absent. In the lower extremities, the tone was more noticeably increased with brisk tendon reflexes, including crossed adductor reflexes, and there was clonus at the ankles. Plantar reflexes were extensor. There was no atrophy nor fasciculations. Strength was symmetric, with the hip flexors being Medical Research Council grade 3+/5; hamstrings 4/5; and ankle dorsi-flexors 4-/5. Knee extensors and plantar flexors were normal in strength. Upper extremity sensation was normal, but proprioception and vibration were mildly decreased in the toes; there was hyperesthesia to pinprick in the feet. There was no
243
sensory level on the trunk, and perianal sensation was normal. Gait was markedly spastic. Laboratory evaluation disclosed a normal ANA titer, and erythrocyte sedimentation rate. Two measurements of vitamin B12 were normal. Serum antibodies to Human T-cell lymphotrophic virus (HTLV-1), Human Immunodeficiency virus (HIV-1), and Hepatitis B virus (HBV) were absent. Hepatitis C virus (HCV) antibody assay was positive, but serum testing for HCV D N A via polymerase chain-reaction was negative. Cerebrospinal fluid (CSF) contained normal glucose, protein, and cell counts. Non-enhanced and gadolinium enhanced MRI of the cervical and thoracic spinal cord revealed no abnormalities. Prior MRI of the brain revealed mild generalized atrophy and no evidence of abnormalities in the white matter. There was mildly increased signal in the bilateral putamen, consistent with changes seen in patients with a history of portal-systemic encephalopathy [1]. Abdominal computed tomography (CT) revealed a cirrhotic liver, thrombosis of the portal vein, and extensive collateralization and varices. Portal vein thrombosis and collateralization was also demonstrated on superior mesenteric arteriography. After several weeks of oral lioresal, he had improved mobility, with decreased spasticity but without significant changes in the remainder of his neurological examination.
3. Discussion 3.1. The clinical features and diagnosis o f hepatic myelopathy
Hepatic myelopathy should be diagnosed only after a thorough evaluation for more common causes of spastic paraparesis, mainly those involving compression or expansion of the spinal cord. A completely normal MRI of our patient's spinal cord excluded such etiologies, including epidural cord compression, intrinsic cord tumor, or infarction. Infection with HIV or HTLV-1 and vitamin B12 deficiency were also absent. Hepatic myelopathy must also be differentiated from other neurological complications of liver disease. NonWilsonian hepato-cerebral degeneration is a permanent, progressive degeneration of the nervous system, causing cognitive, cerebellar, pyramidal, and extrapyramidal dysfunction in various combinations [2-4]. Patients with otherwise uncomplicated cases of hepatic encephalopathy may also exhibit transient upper motor neuron signs. [2,4,5]. In these circumstances, distinction from HM may be impossible until the non-pyramidal neurologic abnormalities abate with correction of the metabolic disturbance. Lockwood remarks on the need to distinguish these processes from the entity now distinctly recognized as 'hepatic myelopathy' or 'portal-
244
J.V. Campellone et al./ Clinical Neurology and Neurosurgery 98 (1996) 242-246
systemic myelopathy' [2]. There are few reported cases of hepatocerebral degeneration in which permanent corticospinal tract dysfunction is the predominant feature. This complication seems to be much less frequent than other neurologic sequelae from hepatic insufficiency. In one of the largest series of acquired hepatocerebral degeneration, Victor et al. reported no such cases among 27 patients they observed [4]. Our patient had the typical clinical features of HM (see Table 1), namely the insidious progression of spasticity and weakness in the lower extremities. Initially, the symptoms may be slightly asymmetric, but will invariably affect both legs and steadily worsen. Most commonly, symptoms will develop after several bouts of hepatic encephalopathy, although rarely myelopathy may be the presenting manifestation of liver failure. The signs of corticospinal tract damage appear to accumulate with each episode, although other neurologic signs resolve completely. Upper extremities are affected minimally, if at all [6-8]. Increased tone and hyperreflexia are the most prominent findings. Various plantar responses have been described, even in patients with ankle and knee clonus. Most cases involving disturbance of sensation or bladder function occurred in patients with concurrent neuropathy, probably from alcoholism [9-12], although incontinence was a presenting symptom in one patient without peripheral neuropathy [13]. For unknown reasons, men comprise the large majority of reported cases. After months, the process plateaus, leaving most patients either dependent upon an assistive device or confined to a wheelchair. The evaluation of patients with HM reveals no significant abnormality on neuroimaging with vertebral roentgenograms, myelography, or MRI. Lumbar puncture usually reveals no abnormalities other than an elevated glutamine level [14,15], although increased protein content is rarely noted [9,16]. Consistent with the clinical absence of lower motor neuron signs, electromyography is unrevealing [17]. Electroencephalography usually demonstrates diffuse slowing during episodes of encephalopathy, although some slowing may persist despite an apparently normal mental status [14,18].
3.2. The pathogenesis of hepatic myelopathy The first recognition of spinal cord pathology in patients with liver failure is attributed to Leigh and Card, who reported a patient with hepatocerebral degeneration and spastic weakness of the lower extremities [19]. Histopathologic study revealed demyelination in the corticospinal tracts and posterior columns in addition to Alzheimer type-II cells and spongy degeneration in the cerebral cortex. The authors attributed the spinal cord demyelination to nutritional deficiency and the findings in the brain to a deficiency of a hepatic product. The patient previously received radiation treatment
for suspected lymphoma, and the relationship of this treatment to the clinical and pathologic findings in this case is unclear, since the radiation field size and amount were not reported. Systemic shunting of portal blood was first associated with neurologic dysfunction in humans in 1954 when Sherlock and colleagues coined the term 'portal-systemic encephalopathy' in their paper describing diverse neurological symptoms in patients with hepatic disease [5]. They correlated degree of symptomatology with serum ammonia levels and suggested that delivery of nitrogen containing substances into the systemic circulation results in nervous system intoxication. The first accounts of typical HM were reported by Zieve and co-workers, who described patients with extreme sensitivity to dietary protein resulting in repeated episodes of hepatic encephalopathy [9,10]. Coma was associated with elevated ammonia levels which responded to protein restriction and intravenous arginine. With each episode of coma, the patients developed cumulative leg weakness and spasticity, except for one patient who had persistent organic brain dysfunction and alcoholism. Surgical portal-systemic shunts were present in these patients for over two years before symptoms of HM appeared, and the authors implicated the shunting as a possible etiologic factor in the development of the permanent neurological sequelae. The authors could not discount the role of gastrectomy, although two similar patients without gastrectomy were subsequently reported by Pant et al. [20] further implying a relationship between HM and shunting. Following increased recognition of this syndrome and possibly due to improved survival among patients with portal-systemic shunts, more descriptions of pyramidal tract dysfunction in liver failure followed [7,2131]. Many of the earlier cases were associated with significant non-pyramidal neurological signs and would more appropriately be classified as examples of hepatocerebral degeneration [4,5,7,22]. Furthermore, patients with atypical features were found to have Wilson's disease at autopsy [29], or there were confounding disorders such as pontine tumors and thoracic vertebral fractures [12]. Regardless, more current descriptions continue to relate portal-systemic shunting to corticospinal tract pathology. Implicated by early authors and further supported by more recent observations, portocaval shunts [5,7,8,1115,21-27,29-31], or less commonly splenorenal shunts [18,30], appear to have a substantive role in the neurologic deterioration. The portocaval shunts can occur either spontaneously, after surgery, or due to 'functional shunting' [7] -- filtration of portal blood through a non-functioning liver. Our patient had both longstanding portocaval shunting and more recent surgical splenorenal shunting. Although the duration between shunting and onset of neurologic symptoms may vary,
J.V. Campellone et al. I Clinical Neurology and Neurosurgery 98 (1996) 242-246
it commonly takes 6-36 months before patients notice difficulty walking; this delay is somewhat longer in patients with splenorenal shunts. Given the apparent relationship to shunting and improvement with protein restriction, many authors have suggested the spinal cord insult is due to nitrogenous toxins that are inappropriately delivered to the systemic circulation [5,10]. Ammonia is the most frequently implicated agent, although mercaptan and other substances are suitable candidates [10,11,14]. Others have suggested that altered spinal hemodynamics secondary to the effects of shunting may be respor~Lsible [25], although there are few data to support this contention. Selective demyelination of the corticospinal tracts is a universal finding in the pathologic studies of patients with HM. In correlation with the clinical descriptions, demyelination first becomes noticeably evident in the low cervical cord and is more prominent in caudal regions. Although the predominant process is demyelination with secondary reactive changes, axonal loss or distortion are occasionaLlly noted [17,18]. Minor abnormalities in the posterior columns [17], spinothalamic tracts, or spinocerebellar tracts [16] are infrequently reported, and are possibly related to alcohol use [17]. The most common finding in patients with liver disease [3,4], the Alzheimer type-II cell, is frequently present in the cerebral cortices [7,10,15,29] and occasionally more diffusely [18,19,21,25] in HIVl patients, despite the absence of clinical correlates. Observations of decreased numbers of Betz cells [17] were not confirmed by others [10,15,16,18], and the pyramidal tracts were noted to be normal as they pass through the internal capsules and brainstem [17,29]. Perivascular lymphocytic infiltrates, lipid-laden macrophages, and neuronal loss in the spinal gray matter [25] were also noted. Vascular structures in the spinal c,ord are routinely normal. Our patient had mildly increased signal in the putamen, a common finding in patients with liver disease[l]. More patients with HM will require study via brain imaging with pathologic correlation before the relevance of this finding is understood.
3.3. Treatment of hepatic myelopathy In most patients, therapy directed at reducing nitrogen absorption was generally unrewarding. Protein restriction [8,13-15,18,301i, oral neomycin [5,8,10,1315,18,20,23,26,30], lactulose [15,26], and colonic exclusion [15,23] failed to produce significant improvement. At best, these measures prevented or decreased the numbers of encephalopathic episodes [6,29]. Even so, progressive paraparesis 'was observed even when encephalopathy was effectively averted. Symptomatic treatment, consisting of lioresal, has improved our patient's ability to ambulate, altlhough others have found this therapy of no benefit [27]. One patient experienced
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more noticeable improvement with a carbidopa/levodopa preparation [13], but this observation has not been duplicated. Administration of flumazenil, a benzodiazepine receptor antagonist, has been demonstrated to temporarily benefit the symptoms of hepatic encephalopathy [32], and the effect of this drug on the course of HM warrants study. We could find no reports of liver transplantation among this patient population. As this procedure becomes more widely performed, symptoms heralding the development of HM may be sufficient to warrant urgent transplantation, given the usually debilitating outcome of this process.
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