Acquired hepatocerebral degeneration: clinical characteristics and MRI findings

Objective: To determine the prevalence of acquired hepatocerebral degeneration (AHD), its clinical and neuroimaging characteristics and response to treatments. Background: Acquired hepatocerebral degeneration is a chronic encephalopathy with predominant motor signs in the context of severe liver disease. Its clinical picture is not well defined, and its prevalence and risk factors are not well known. Methods: Review of a database of 1000 patients with cirrhosis to identify cases of AHD. Clinical and neuroimaging data, follow‐up and response to treatments, including liver transplantation, were recorded. Results: Eight patients with AHD were identified. Its prevalence was 0.8% of patients with cirrhosis. The main risk factor for AHD was the presence of portosystemic shunts. Movement disorders, especially a combination of parkinsonism and cerebellar signs were observed in all patients. All AHD cases showed on MRI T1‐weighted images hyperintensities in the globus pallidus, and 75% had extrapallidal involvement as well. Antiparkisonian drugs and treatments to prevent acute encephalopathies were ineffective. Three patients who underwent liver transplantation did not experience neurological improvement. Persistence of portosystemic shunts was demonstrated in two cases. Conclusions: Acquired hepatocerebral degeneration is a chronic encephalopathy which occurs in ～1% of patients with liver cirrhosis and seems related to portosystemic shunts. Its is characterized by a combination of parkinsonism and cerebellar signs. MRI pallidal and extrapallidal lesions are seen in most patients, probably reflecting intracerebral deposits of manganese. Liver transplant did not improve the neurological signs in our patients, perhaps because of the persistence of portosystemic shunts.     

Acquired hepatocerebral degeneration and hepatic encephalopathy: correlations and variety of clinical presentations in overt and subclinical liver disease

Acquired hepatocerebral degeneration (AHD) and hepatolenticular degeneration can have similar clinical presentations, but when a chronic liver disease and atypical motor findings coexist, the distinction between AHD and hepatic encephalopathy (HE) can be even more complicated. We describe three cases of AHD (two having HE) with different neuroimaging findings, distinct hepatic diseases and similar motor presentations, all presenting chronic arterial hypertension and weight loss before the disease manifestations. The diagnosis and physiopathology are commented upon and compared with previous reports. In conclusion, there are many correlations among HE, hepatolenticular degeneration and AHD, but the overlapping of AHD and HE could be more common depending on the clinical knowledge and diagnostic criteria adopted for each condition. Since AHD is not considered a priority that affects the liver transplant list, the prognosis in AHD patients remains poor, and flow interruption in portosystemic shunts must always be taken into account.     

Hepatic encephalopathy coexists with acquired chronic hepatocerebral degeneration

Hyperkinetic extrapyramidal syndrome is the typical clinical characteristic of acquired hepatocerebral degeneration (AHD), but is usually not observed with hepatic encephalopathy (HE). We present a case of AHD coexisting with HE. Both conditions were secondary to liver cirrhosis and hepatitis C virus infection. The brain MRI showed bilateral and symmetric high T1 signal-intensity in the globus pallidus, and diffuse high signal-intensity of the hemispheric white matter on T2-FLAIR images. As we usually neglect the existence of AHD, the diagnosis is often ignored, especially when it coexists with HE. This case highlights the need to distinguish irreversible AHD from HE.Progressive chronic liver disease often causes neurological manifestation, including hepatic encephalopathy (HE), acquired hepatocerebral degeneration (AHD), and hepatic myelopathy (HM). Among these dysfunctions, HE is the most common and reversible disorder, while AHD is a rare and irreversible syndrome. Hepatic encephalopathy is a serious complication of liver disease and is characterized by neuropsychiatric symptoms, which range from subtle neurocognitive alterations to severe life-threatening neurological impairment.1,2 Hepatic encephalopathy presents in as many as 28% of patients with liver cirrhosis, and can be alleviated by lowering the blood ammonia levels.1,2 However, AHD is rare and the best result among the possible treatments is orthotopic liver transplantation.3 The prevalence of this disease is between 0.8-2% of cirrhotic patients. Of note, the more relevant risk factors are the presence of portosystemic shunts and the multiple bouts of hepatic coma seen in some patients with HE.4,5 Acquired hepatocerebral degeneration is a progressive, irreversible neurological syndrome caused by persistent and decompensated liver disease, and characterized by abnormal movements, dysarthria, rigidity, intention tremor, ataxia, and impairment of intellectual functions.6 In AHD physiopathology, manganese accumulation in the basal nuclei appears to be a key factor. This metal concentration is responsible for the MRI T1 hyperintensity mainly involving the basal ganglia, which can be considered a biomarker of manganese overload.3,6 Hepatic encephalopathy and AHD are 2 different CNS disorders secondary to hepatic dysfunction. Hyperkinetic extrapyramidal syndrome is the typical clinical characteristic of AHD, but usually not observed in HE. Here, we describe a case coexisting with HE and AHD in the presence of symmetrical basal ganglia high signal intensity on T1-weighted images and widespread T2 high signal intensity of the hemispheric white matter. Our objective in presenting this particular case is to highlight the presence of AHD that is considered rare as the diagnosis tends to be ignored.     

Features of cell death in brain and liver,the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease)

Alpers-Huttenlocher disease (AHD) is a rare encephalopathy of infancy and childhood characterized by myoclonic seizures and progressive neurological deterioration, usually associated with signs and symptoms of liver dysfunction. There is no biological marker of the disease, and ultimate diagnosis still relies on pathological examination. Features of clinical progression and pathological findings suggest AHD to be secondary to a genetically determined disorder of mitochondrial function. We report on four AHD patients and focus on their pathological features in brain, liver and muscle. Liver and muscle biopsy specimens were examined using histochemical markers of the oxidative pathways, probes to immunodetect molecules of the apoptotic cascades and electron microscopy. In liver (but not in muscle) biopsy samples, activated caspases were detected by immunohistochemistry: foci of caspase-9-positive cells were seen in a child affected with chronic, progressive fibrosis. In an 18-year-old boy, who suffered from valproic acid-associated acute hepatitis, caspase-3 cells were clustered among the necrotic foci and the foamy cells. In both patients electron microscopy revealed apoptotic nuclei. Normal muscle biopsy specimens were observed in two children, 2 and 8 years-old respectively; in the 18-year-old patient cytochrome oxidase-negative fibers as well as ultrastructural findings of mitochondrial abnormalities were observed. In no patient was there biochemical evidence of impaired oxidative metabolism. Neuropathological examination of the brains of two patients (13 months and 19 years old, respectively) showed focal distribution of the lesions affecting the telencephalic cortex and, to a lesser extent, subcortical gray nuclei. Along with the necrotizing lesions, characterized by neuronal loss, neuropil microcysts and newly formed vessels, we also observed acutely shrunken neurons and features of apoptotic cell death in the cerebral cortex only. Severe neuronal loss without necrotizing features was observed in the cerebellar cortex. The presence of both anoxic and apoptotic nuclei in brain and liver, the target tissues of the disease, is consistent with the hypothesis that abnormal activation of mitochondrion-related cell death pathways might be involved in the pathogenesis of AHD.     

获得性肝脑变性的临床与影像学特点

目的分析获得性肝脑变性的临床和影像学特征，探讨其规律性。方法分析9例获得性肝脑变性病例的临床表现、实验室检查和影像学改变的数据。结果5例既往有明确的肝硬化病史，4例没有明确的肝病病史，发病后检查分别发现肝血管病、肝胰脾等弥漫钙化或者肝硬化。主要临床表现为：精神异常、认知能力下降、帕金森病样综合征、构音障碍、共济失调、睡眠障碍。肝酶学轻中度异常，而血氨均升高。脑电图提示脑电活动呈弥漫性减慢，4例出现三相波节律。影像学改变为苍白球、大脑脚、小脑和大脑皮层下对称性短T1加权像信号，以及基底节、中脑、脑桥、延髓橄榄核对称性长T2加权像信号。结论获得性肝脑变性是肝细胞和肝血管病变引起的神经功能损害综合征，肝酶改变、血氮升高和脑电图符合代谢性疾病改变，结合特征性影像学改变，对疾病的诊断具有重要意义。     

The academic half-day in Canadian neurology residency programs

BACKGROUND: The academic half-day (AHD) appears to have become widespread in Canadian neurology residency programs, but there is little published information about the structure, content, or impact of the AHD. METHODS: A written questionnaire was sent to the directors of all active Canadian adult and child neurology residency programs. RESULTS: All 21 program directors responded. An AHD was operating in 15/15 adult and 5/6 child neurology programs. The AHD typically lasts three hours, and occurs weekly, 10 months per year. Most of the weekly sessions are lectures or seminars, usually led by clinicians, with about 90% resident attendance. Course-like features (required textbook, examinations) are present in many AHDs. There is a wide range of topics, from disease pathophysiology to practice management, with considerable variation between programs. CONCLUSIONS: Almost all Canadian neurology programs now have an AHD. Academic half-days are broadly similar in content and format across the country, and residents now spend a substantial portion of their training attending the AHD. The impact of the AHD on how residency programs are organized, and on the learning, clinical work, and professional development of residents merits further study.     

戒断期海洛因依赖者额叶认知功能的功能磁共振成像研究

目的 研究戒断期海洛因依赖者(AHD)的脑认知功能.方法 采用3.0 T磁共振成像系统,对30例AHD(AHD组)和18名健康对照者(对照组)在完成Go/NoGo任务时行全脑功能磁共振成像(fMRI)扫描,记录反应时间(RT).结果 (1)RT:AHD组在完成Go/NoGo任务时的RT[(394±34)ms]长于对照组[(374±26)ms;P<0.05].(2)fMRI:对照组在完成Go/NoGo任务时,诱发激活双侧前额叶内侧回、前扣带回以及双侧额下回等脑区;AHD组全脑活动普遍低,仅有双侧额上回和左侧额中回激活.两组间比较,AHD组激活显著低于对照组的区域主要位于在双侧额内侧回、前扣带回、额下回及双侧颞叶等脑区(P<0.005).结论 戒断期海洛因依赖者反应抑制功能障碍仍然存在,促进其认知功能的恢复可能成为戒毒、抗复吸的有效策略.     

Antigen-dependent alterations in the lipid composition of the CNS in guinea pigs with experimental allergic encephalomyelitis

Stimulation of LH release following electrochemical stimulation (EC) of median eminence-arcuate region (ME-ARC) during various stages of 5-day estrous cycle of rat has been studied. On day 2 post-ovulation (diestrus II), when the vaginal smear consisted of leucocytes, elevations in plasma LH as a result of ME-ARC stimulation were minimal. With the change in vaginal smear to nucleated epithelial cells on day 3 (proestrus I) and cornified cells on day 4 (proestrus II) post-ovulation EC stimulation induced significantly higher elevations in plasma LH than those obtained following stimulation on diestrus II. To determine whether neural links between medial preoptic area and ME-ARC are essential during the period in which the marked changes in sensitivity of ME-ARC to EC stimulation occur, the anterior hypothalamus was partially deafferented (AAD) in rats at various stages of the estrous cycle.Plasma LH levels following EC stimulation of ME-ARC at 18.00 h of proestrus I were assessed in these AHD rats. LH levels were found to be correlated with cell types present in the vaginal smear at the time of EC stimulation. Nucleated epithelial cells were present at the time of stimulation in rats deafferented at 09.00 h of proestrus I or 18.00 h of diestrus II and in 5/9 rats at 08.00 h of diestrus II similar to the control rats in which sham AHD was performed at 09.00 h of fiestrus II or of proestrus I. Elevations in plasma LH after stimulation in these rats were comparable to those observed in sham AHD control rats. Quite different results were obtained when AHD was performed at 17.00 h of diestrus I or at 08.00 h of fiestrus II (4/9 rats). Vaginal smear consisted of leucocytes; and slight elevations of plasma LH after stimulation of ME-ARC were detected. However, administration of estradiol benzoate (5 μg/rat) 12 h after AHD at diestrus I not only induced cornification of vagina but also restored the plasma LH values to those obtained following stimulation of ME-ARC of intact or sham AHD control rats. These results indicate that maximal LH release following ME-ARC stimulation of deafferented rats requires estrogen priming.     

PRL and ACTH secretion following acute heat exposure, in intact and in hypothalamic deafferentated male rats

Adult male rats, intact or bearing complete, anterior or posterior hypothalamic deafferentiations (CHD, AHD AND PHD, respectively) were acutely exposed to environmental temperature of 36 degrees C, and serum PRL and ACTH concentrations were determined by RIA. In intact animals, heat exposure resulted in elevated serum PRL and ACTH levels. None of the deafferentations affected basal serum PRL concentrations, whereas those of ACTH were elevated in both CHD and AHD, but not in PHD groups, as compared to intact controls. The PRL heat response was completely absent in CHD, attenuated in AHD, and delayed in PHD animals, and the ACTH heat response was absent in all three groups. These results demonstrate (1) that acute exposure to elevated environmental temperature stimulates secretion of PRL and of ACTH; (2) that this stimulation is carried out by diverse neural pathways; and, (3) that hypothalamic modulation of the secretion of PRL and ACTH is effected by independent mechanisms.     

Early tolerability of Comirnaty vaccine in patients with chronic neurological diseases

Patients with chronic neurological diseases may have predisposing risk factors for severe COVID-19 and should be considered as priority candidates for SARS-CoV-2 vaccination. Nevertheless, the safety of RNA vaccine was evaluated in healthy volunteers or in patients with stable chronic medical conditions excluding patients with chronic neurological diseases. We report here the early tolerability of Comirnaty vaccine in 36 patients with chronic neurological diseases and demonstrate good early tolerability, better than found in healthy people in phase 3 trials.     

Memory disorders associated with huntington''s disease: Verbal recall, verbal recognition and procedural memory

Two experiments were conducted to evaluate the hypothesis that the memory disorders of Huntington's Disease (HD) patients are characterized by deficiencies in both retrieval mechanisms and the acquisition of procedural (skill-based) information. In the first study, verbal recall and recognition tests were administered to HD patients, amnesics and normal control (NC) subjects. Although the two patient groups were impaired relative to NC subjects on both recall and recognition of word lists, the performance of the HD patients was superior to that of the amnesics on the recognition test. In the second experiment early HD (EHD), advanced HD (AHD), amnesic and NC subjects were compared in the acquisition of the ‘Tower of Hanoi’ puzzle. Both the NC subjects and EHD patients acquired the solution of this puzzle after repeated trials, whereas the AHD and amnesic patients evidenced little improvement. However, on a recognition test assessing memory for facts about the puzzle, both the EHD and AHD patients were superior to the amnesic subjects. These results are consistent with the retrieval hypothesis but are equivocal with regard to the HD patients' proposed deficit in skill learning. Since the ‘Tower’ puzzle may rely heavily on both problem solving and skill learning capabilities, it may be of limited value in searching for double dissociations between patient groups and the acquisition of skill-based and data-based knowledge.     

Central-peripheral sensory axonopathy in a juvenile case of Alpers-Huttenlocher disease

Peripheral ataxia is reported in a juvenile case of Alpers-Huttenlocher disease (AHD). Neurophysiological and neuropathological investigations revealed a central-peripheral axonopathy, affecting the deep sensation carried by the peripheral nerve fibres and the posterior tracts of the cord, due to neuronal loss of the sensory ganglia. Involvement of the sensory pathways is regarded as a major feature of juvenile AHD. Received: 28 October 2002, Received in revised form: 2 January 2003, Accepted: 15 January 2003 Present address: A. Polo, MD, Neurology Unit, Hospital of Piove di Sacco (PD), Italy Correspondence to: A. Simonati, MD     

Corticotrophin and corticosterone secretory patterns following acute neurogenic stress, in intact and in variously hypothalamic deafferented male rats

Adult male rats, intact (N) or bearing complete (CHD), anterior (AHD), or posterior (PHD) hypothalamic deafferentations, were acutely exposed to either visual or audiogenic stimulation. At 2, 4, 10 or 30 min following the onset of stress exposure the animals were decapitated and trunk blood was collected for ACTH (RIA) and corticosterone (CS, CBG) determinations. Basal serum concentrations of both hormones were elevated in CHD and AHD, but not in PHD animals as compared to N animals. In N rats, exposure to both stresses resulted in elevated serum ACTH and CS concentrations, with the ACTH response to audiogenic but not visual stimulation being biphasic. In CHD animals, serum ACTH concentrations decreased, and those of CS were unchanged following stress exposure. While audiogenic stimulation caused elevation in serum levels of both hormones in AHD rats, the normal ACTH and CS response to visual stimulation were completely abolished by anterior hypothalamic deafferentation. In PHD animals, no ACTH response to either of the stress exposure was apparent; in spite of this, partial CS responses were elicited. These data thus describe the temporal aspects of the ACTH and CS secretory responses to different neurogenic stresses, and provide insight into the neural pathways mediating these responses.     

A temporal study of post-adrenalectomy increase in ACTH secretion in the rat: effect of various hypothalamic deafferentations

Adult male rats, intact (N) or with complete (CHD), anterior (AHD), or posterior (PHD) hypothalamic deafferentations were bilaterally adrenalectomized. At 3, 6, 12 and 20 days post-adrenalectomy they were decapitated and trunk blood was collected for ACTH determinations. In N rats, ACTH markedly elevated up to 850 pg/ml. A similar ACTH response was found in PHD rats but the values were lower by approximately 20%. In contrast, in either AHD or CHD rats, ACTH responses were markedly attenuated and reached a plateau of about 350 pg/ml. These data suggest that: (1) neural inputs entering the medio-basal hypothalamus (MBH) from both the caudal and rostral directions are important for obtaining maximal ACTH responses following adrenalectomy; (2) at least part of this ACTH response is mediated by sites inside the MBH or in the pituitary.     

Clinical pathways for non-acute neurological diseases as amyotrophic lateral sclerosis

Clinical pathways are integrated plans of tasks dedicated to obtain the major benefit for the patients, considering all aspects of the management, as the role of physicians and nurses and standardizing the procedures in forms and time. Their interest has grown since the developing of clinical management models. In neurological diseases their use has been restricted to acute phases, and in the case of chronic neurological diseases for specific techniques. The authors analyze the interest of the design and use of clinical pathways for chronic neurological diseases starting from the paper from Rodriguez de la Rivera et al. on a clinical pathway for amyotrophic lateral sclerosis. For the authors, the specific differences between clinical pathways for acute neurological diseases and chronic diseases are changes in the design of temporal matrix using stages, multispeciality teams, the standardised access to social benefits and the role of case-manager, as professional who maintain a direct relation with patients. The authors also approach the setting difficulties in the development of clinical pathways that should be greater in the chronic neurological disease and suggest the role of scientific societies in their promotion.     

Human T lymphotropic virus type I (HTLV-I) infection in neurological patients in Salvador, Bahia, Brazil.

HTLV-I infection represents a major health concern in endemic areas throughout the world, such as Salvador, the main city of Bahia State, with socio-demographic characteristics similar to sub-Saharan African cities, located in the Northeast of Brazil. In order to provide an estimate of the frequency distribution, and range of neurological manifestations potentially related to HTLV-I infection in this city, we conducted a cross-sectional clinical-epidemiological study to determine the prevalence of this infection in patients with neurological diseases. Patients exhibiting vascular diseases, tumoral diseases or trauma were excluded. Over a period of 16 months, we studied 322 consecutive patients with chronic neurological diseases, who attended the neurological clinics of two major hospitals in Salvador. Overall, the prevalence of HTLV-I infection among the patients was 20.9% (67/320). However, the prevalence among the 104 patients with chronic myelopathy was 50.0% (52/104). It was observed that the major prevalence of HTLV-I was between the ages of 40 and 60 years with a female predominance. Our data indicate that, in Salvador city, HTLV-I is associated with chronic myelopathies or myeloneuropathies, which seem to be the only neurological diseases associated with HTLV-I.     

Chronic relapsing demyelinating encephalomyelitis associated with persistent spontaneous canine distemper virus infection

Summary This is the first report of spontaneous canine distemper virus (CDV) infection in a dog associated with chronic progressive multiphasic neurological disease. Initial neurological deficits in the pelvic limbs progressed rapidly to paraplegia with almost complete remission after 9 weeks. Then another acute episode occurred with severe thoracic limb deficits and cerebellar dysfunction and progressive neurological deterioration over 3 months with rising serum neutralizing (SN) anti-CDV titers in the serum and cerebrospinal fluid (CSF). Three neuropathologically distinct lesions of spinal cystic necrosis, chronic demyelinating foci in the cerebellum and acute demyelinating encephalitis in the pons were identified. Persistent CDV antigen was demonstrated immunocytochemically only in acute lesions and atypically restricted to neurons. However, the immunological mechanism associated with the distinct remissions and exacerbations and CDV antigen clearance from chronic demyelinating lesions but persistence in acute lesions, despite a vigorous anti-CDV serologic response, was not defined.     

Psychiatric and neurological effects of chronic solvent abuse.

This study is a review of the psychiatric and neurological effects of solvent inhalation on a group of 22 patients with chronic histories of solvent abuse, primarily toluene-based solvents. The findings suggest that the chronic inhalation of toluene-based adhesives can produce a paranoid psychosis which may persist. Other findings were a high incidence of temporal lobe epilepsy and decrease in IQ. We suggest that the psychiatric and neurological sequelae of chronic solvent abuse are serious and potentially irreversible. Toluene is felt to be a major factor in the morbidity associated with chronic solvent abuse, and attention is drawn to the necessity for educational programs in this area. The burden caused by the resulting psychiatric problems resulting from solvent abuse may have implications for health care budgets.     

Schmerz – ein vernachlässigtes neurologisches Thema

Chronic pain represents a great challenge; according to epidemiological data increasing numbers of patients should be expected. Based on recent advances, a better understanding of the pathophysiology of chronic pain has been achieved and neurologists have made a major contribution to this understanding. Chronic pain is accompanied by substantial maladaptive plastic alterations in both the peripheral and central nervous systems; therefore, neurological knowledge is of paramount importance for pain therapists but this contrasts with the current treatment situation of pain patients in Germany. There are basically too few departments and practices undertaking treatment, and neurologists are an exception in most pain centers. Furthermore, due to economic reasons neurological hospitals are currently experiencing a dearth of inpatients suffering from chronic pain. Diagnostic and/or treatment procedures for neurological pain entities (e.g. headaches or neuropathic pain) are insufficiently represented in the German diagnosis-related groups (DRG) reimbursement system and the obstacles for an efficient pain therapy in neurological practices are too high. Finally, there are too few academic positions for pain medicine in neurological hospitals; therefore, career opportunities for motivated young neurologists with an interest in pain are lacking. In order to address the unmet therapeutic needs of patients with chronic pain there is a high demand for (i) establishment of departments for neurological pain medicine, (ii) modification of the German DRG system and (iii) education of young neurologists with expertise in pain. Pain medicine in particular should be especially appealing to neurologists .