Neurological manifestation of hepatic diseases

Dr. Parag MoonSenior resident,

Dept. of Neurology,GMC, Kota

Hepatic encephalopathy Hepatocerebral degeneration Hepatic myelopathy Cirrhosis-related parkinsonism Cerebral infections Cerebral Hemorrhage Osmotic demyelination.

In addition, neurologic complications can be exclusive to certain disorders, for example, Wilson disease, alcoholism (Wernicke encephalopathy, alcoholic cerebellar degeneration, Marchiafava-Bignami disease, etc), hemocromatosis etc

Syndrome of neuropsychiatric, neuropsychological and neurological disturbances that may arise as a complication of liver disease.

Reversible complete or incomplete. 10-50% of liver disease- overt hepatic

encephalopathy in lifetime.

Hepatic encephalopathy (HE)

Nomenclature of HE

Ferenci P et al ;Hepatology :2002.

Multifactorial pathogenesis Combination of chronic low-grade glial

oedema and potentiation of effects of gamma amino butyric acid (GABA) on CNS by ammonia.

Increase in GABA release Enhanced activation of GABA-A receptor

complex. Increased concentrations of endogenous

benzodiazepines-found in brain in liver failure

Pathogenesis

Ammonia- neurotoxic, but at higher levels than those found in liver failure

It tends to cause neuronal excitation. At lower concentrations, potentiates

actions of GABA, possibly by enhancing ligand binding to GABA-A receptor complex.

It reduces glutamate synthesis and down-regulates glutamate receptor in vitro-reduced excitatory transmission in brain.

Fulminant hepatic failure-levels of ammonia tend to be higher

May contribute to neuroexcitatory symptoms seen-agitation, seizures and multifocal muscle twitching via direct toxicity.

Ammonia-adverse effect on osmoregulation via its reaction with glutamate to form glutamine-exacerbating cerebral oedema

Dopaminergic, serotonergic and opioid neurotransmitter systems-pathogenesis of HE.

Mechanisms for cerebral edema Breakdown of blood-brain barrier (vasogenic

oedema) Impaired cellular osmoregulation (cellular or

cytotoxic oedema) In later stages there is loss of cerebral

autoregulation.

In fulminant hepatic failure autopsy reveals brain oedema and astrocyte swelling.

In cirrhosis and portal-systemic shunts-Alzheimer type II astrocyte-pathological hallmark of HE.

Found in cortex and lenticular, lateral thalamic, dentate and red nuclei.

Abnormal astrocytes-shown to be produced by ammonia.

Increased levels of manganese in basal ganglia and to a lesser extent other areas of brain.

Sleep disturbance most common early signs-50% of cases.

Derangement of consciousness accompanied by decreased (or occasionally increased) psychomotor activity through increasing drowsiness, stupor and coma.

Asterexis- common but nonspecific Signs of pyramidal tract dysfunction initially

eventually being replaced by hypotonia Seizures- rare.

Clinical features

HE differ from other metabolic encephalopathies in early stages-striking Parkinsonian syndrome

Correlate with degree of T1 hyperintensity in basal ganglia, changes in choline/creatine ratios.

Focal neurological deficits rare. Visual disturbances-result of cortical and retinal

dysfunction. Hepatic retinopathy-damage to retinal glia or

Muller cells.

Clinical stages of HE

Jones EA et al; JNNP; 1997

Routine investigation Arterial blood ammonia-usually raised, level

bears little relation to severity of HE. EEG- triphasic waves, non specific Visual (VEP), sensory (SEP) and brainstem

auditory (BAEP) evoked potentials- delayed latencies (a slower response) which become more prolonged in relation to degree of HE.

Lumbar puncture- not indicated. Neuroimaging-if doubt.

Diagnosis

Supportive. Precipitating factors-treated or removed Reduction of absorption of nitrogenous

substances from intestinal tract-evacuation of bowel by purgation, enemas, elimination of dietary protein

Oral Lactulose Mannitol Gut sterilization- Rifaximin, neosporin Hepatic transplantation.

Treatment

Nursed supine with head and upper body raised 20°-30° above horizontal

Psychomotor agitation- small dose of BZD (oxazepam) or small dose of morphine

Measurement of ICP- Epidural catheters if coagulopathy other wise intraventricular device in fulminant hepatic failure.

ICP be maintained below 20 mm Hg

Oral protein load Upper gastrointestinal

bleed Constipation Diarrhoea and vomiting Dehydration Electrolyte and

acid/base imbalance Diuretic therapy Abdominal

paracentesis

Hypoxia Hypotension Anaemia Hypoglycaemia Sedative/hypnotic drugs Azotaemia Infection Induction of medical or

surgical portal-systemic shunt

General surgery

Precipitating factors

Flumazenil Central BDZ antagonist with weak partial agonist

action(1) Often reproducible in individual patient; (2) occur in only about 60%(3) Occur rapidly, within four minutes of drug administration; (4) substantial ameliorations occur after low doses—0.3-0.5

mg(5) short duration(6) usually partial (for example, one or two clinical stages). (7)improve cognitive component in subclinical hepatic

encephalopathy.

Disadvantages of flumazenil-◦ Partial agonistic action, mechanism other than

increase GABAnergic tone Levodopa, bromocriptine and infusions of

branched chain amino acids-false neurotransmitter hypothesis

Results unconvincing

Mortality high at around 70–80% in fulminant hepatic failure

Following first episode of overt hepatic encephalopathy-1-year survival 40%

15% after 3 years.

Prognosis

Replaced old terms of latent or sub-clinical hepatic encephalopathy.

Affect between about 20% and 70% of patients

Impairment of visuospatial functioning, attention and psychomotor speed

Critical flicker frequency Constructional apraxia Neuroimaging Evoked potential

Minimal hepatic encephalopathy

Acquired (non-Wilsonian) hepatocerebral degeneration (AHCD)

Originally characterised by Victor et al. in 1965. Chronic and irreversible. Typical clinical features-dementia, dysarthria,

ataxia of gait, intention tremor and choreoathetosis.

Diffuse but patchy cortical necrosis, diffuse proliferation of Alzheimer type II glial cells and uneven neuronal loss in cerebral cortex, basal ganglia and cerebellum

Acquired hepatocerebraldegeneration and hepatic myelopathy

Hepatic or portal-systemic myelopathy (HM)

Described Zieve et al. in 1960 Spastic paraparesis with minimal sensory

involvement. Symmetrical demyelination, predominantly

of lateral pyramidal tracts, sometimes associated with axonal loss, generally going no higher than cervical cord level

Pathogenesis poorly understood Nitrogenous products bypassing liver

through porto-caval shunt play an important role.

AHCD -represents damage accumulated from multiple episodes of hepatic encephalopathy.

Chronic exposure to toxic substances bypassing liver-causes both AHCD and HM.

Pathogenesis

Treatment difficult. Case reports of transplantation being used

with varying degrees of success. In early stages, demyelination seems to

predominate As disease progresses axonal loss occurs,

and is likely to be irreversible. Case reports suggest- transplantation done

within 10 months-good clinical outcome. TIPSS- may increase AHCD

Treatment

Unique, consistent, and common subset of acquired hepatocerebral degeneration

Abnormal manganese (Mn) deposition in BG Increased dopamine metabolism with

decreased D2 dopamine receptor density, Altered glutamate- or γ-aminobutyric acid–

mediated neurotransmission, Reduced glucose consumption in BG.

Cirrhosis related parkinsonism

Rapidly evolving and symmetric akinetic-rigid syndrome

Early gait and postural impairment Focal dystonia in 50% Resting tremor notably minimal or absent Postural tremor prominent. Oculomotor, cerebellar, pyramidal, or

sensory abnormalities lacking.

Cognitive functions globally preserved except for some degree of frontal lobe dysfunction

No prominent psychiatric features except mild depression.

Insidious onset and rapid progression over months until parkinsonism reaches a plateau, followed by chronic and more stable course over years.

Parkinsonism develops independently and separately from HE episodes

Appearance of parkinsonism- more related to degree of liver failure rather than to specific cause.

Trials show good response to levodopa suggestive presynaptic defect.

Central pontine myelinolysis and extrapontine myelinolysis-osmotic demyelination disorders.

Not exclusive to liver disease More common in association with liver

disease, particularly alcoholic liver disease.

Osmotic demyelination disorders

Central pontine myelinolysis-rapidly evolving paraparesis or quadraparesis, pseudobulbar palsy and impaired responsiveness.

Pathologically-loss of myelin in basis pontis, often in strikingly symmetrical fashion

Neurological impairment range from minimal symptoms to full ‘locked in’ syndrome

Most cases involve a change in osmolality, often rapid and often involving correction of hyponatraemia but not all cases.

Pruritus of cholestasis may at least in part have its origins in CNS.

Several mechanisms : 1. opioid agonists induce pruritus by a central

mechanism, 2. central opioidergic tone is increased in

cholestasis 3. opioid antagonists can improve symptom.

Peripheral neuropathy More common with alcohol, hepatitis C,

porphyria Worse liver disease, worse neuropathy,

independent of aetiology Suggests-liver disease itself is causing, or at

least contributing to neuropathy.

MRI- abnormally high signal on T1-weighted imaging in basal ganglia, particularly globus pallidus

Believed to be due to manganese deposition Chronic manganese poisoning produces

syndrome very similar to AHCD AHCD-more extensive high signal in white

matter on T2-W. Hepatic myelopathy-usually no MRI

abnormalities

Neuroimaging abnormalitiesassociated with liver disease

THANK You

Neurologic Presentations of Hepatic Disease; Harris, Meghan K. et al.;Neurologic Clinics; 2010; Volume 28 , Issue 1 , 89 - 105

Burkhard PR, Delavelle J, Du Pasquier R, Spahr L. Chronic Parkinsonism Associated With Cirrhosis: A Distinct Subset of Acquired Hepatocerebral Degeneration. Arch Neurol.2003;60(4):521-528. 

The neurology of liver failure; M. LEWIS and P.D. HOWDLE; Q J Med 2003; 96:623–633

Neurology and the liver; E A Jones, K Weissenborn;Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:279–293

Sherlock diseases of liver and biliary system.

References