Wet Brain: Alcohol and the Brain - delirium, confabulation, amnesia, and collapse.
In this seminar, Dr Paul Haber looked at the ways alcohol affects the brain, both “direct” effects (intoxication, dependence, withdrawal, hallucinosis and sleep disturbance) and “indirect” effects, ranging from Wernicke-Korsakoff Syndrome to head injury, stroke, intracranial haemorrhage and epilepsy.
The corpus callosum, cerebellum and mamillary bodies are areas of the brain most prone to the effects of alcohol, but indeed the whole brain is sensitive to the effects of alcohol. The extent of this susceptibility is perhaps best seen in the globally impaired brain development of the foetal alcohol syndrome.
(Dr Haber reminded us to be vigilant: FAS is often first diagnosed in adulthood, and that even late identification and management may improve people’s functioning in life.)
Multiple pathology is the rule rather than the exception, even when only alcohol is the injurious agent (as opposed to injury, cerebrovascular disease, hypertension, thiamine deficiency etc).
While dopaminergic and opioid neurochemical in the “brain reward pathways” underlie the phenomena of dependence and craving, the syndrome of alcohol withdrawal results from alcohol’s effects at ligand-gated ion channels, especially GABA-A & NMDA receptors. Adaptive changes in response to chronic alcohol consumption, including desensitization of GABA-A and up-regulation of NMDA receptors, lead to the hyperexcitable state of the CNS in alcohol withdrawal.
Alcohol withdrawal seizures are an important example of this CNS hyperexcitability. They tend to occur in the first 24 hours of alcohol withdrawal and 90% occur within 48 hours. They occur in 10% of hospital series of alcohol withdrawal (they may be less common in community practice). Risk is proportional to the prior level of alcohol consumption. They are generalised tonic-clonic in 95%, and most are uncomplicated and self limiting, however they are multiple in 25%. The EEG is normal in 90% of cases. Seizures are more likely to happen in people who are metabolically unwell. Alcohol also predisposes to seizures in epilepsy and to brain injury which can be a cause of seizures.
Benzodiazepines are effective treatment for alcohol withdrawal (see Cochrane review, Amato et al 2010). Further, in a study of chronic alcohol users who presented to Boston emergency departments after a witnessed, generalized seizure, treatment with intravenous lorazepam was associated with a significant reduction in the risk of recurrent seizures (D’Onofrio et al, N Engl J Med 1999 340:915-9.)
We were reminded that in ambulatory settings, claims to have had alcohol-related seizures may more commonly come from people trying to get benzodiazepines, than from true cases.
Dr Haber mentioned alcoholic hallucinosis, a rare syndrome (0.6% hospitalised alcoholics; Soyka 2008) which needs to be distinguished from the hallucinations of delerium tremens (DTs) and also from alcohol-related psychotic disorder. They are typically auditory hallucinations, and may be accompanied by paranoia, but with preserved insight. The key to diagnosis is that they occur with a clear sensorium. They may occur while drinking and persist during withdrawal, but the majority settle with abstinence. (Dr Peter Tucker however reminded us that most cases of people hearing voices while drinking alcohol will be chronic schizophrenics, as this condition is relatively common and many schizophrenics “self-medicate” with alcohol and other drugs).
Another organic brain syndrome related to alcohol is hepatic encephalopathy. There may be impaired cognitive function, but importantly, this is reversible in early stages, and treatment with lactulose is effective. Most people with hepatic encephalopathy are jaundiced, but bilirubin excretion may be preserved: the mechanism of encephalopathy involves porto-systemic shunting.
The essential neuropathology of direct alcohol-related brain damage is white matter atrophy with reduced brain weight. Myelination and axonal integrity are involved. There can also be grey matter neuronal loss, and large neurons are most susceptible, the same neurons affected by Alzheimer’s disease and ageing. These changes are reversible in experimental animals with alcohol abstinence.
Alcohol is toxic to the brain independent of thiamine deficiency, but the latter probably causes most of the problem we see in clinical practice, including the Wernicke-Korsakoff syndrome (WKS).
Thiamine pyrophosphate is a co-factor in oxidative decarboxylation of α-keto acids. Plant seeds are the major dietary source, but thiamine is removed in processing of white flour and rice. Dr Haber mentioned Dr Clive Harper, of Sydney University, who lead the battle to supplement Australian flour with thiamine, leading to a reduced incidence of
deficiency states.
Dr Harper’s recent review of “The neuropathology of alcohol-related brain damage” (Alcohol. 2009 Mar-Apr 44(2):136-40.) is available free on Pubmed at http://www.ncbi.nlm.nih.gov/pubmed/19147798
Thiamine is highly water soluble, and is lost in cooking. Average requirements are 1 mg/day. Heavy users of alcohol have reduced dietary intake, reduced absorption and increased requirements, partly owing their unbalanced, carbohydrate heavy diets.
The classic triad of Wernicke’s enecephalopathy is present in only 10% of cases, so many cases probably go undiagnosed, or are first diagnosed at autopsy. Confusion is the most common manifestation, with ataxia present in 23% and nystagmus in 29% (with or without horizontal gaze or other palsy)
Wernicke’s is a medical emergency: rapid treatment with parenteral thiamine is highly successful, as the changes are largely reversible, while delayed treatment may result in permanent severe disability.
A Cochrane review concluded there is insufficient evidence to guide treatment with thiamine (other than to say 200mg better than 5mg!). However, the usual practice is to give it prophylactically in all alcohol users admitted to hospital, as 100mg tds 3-5 days, then 100mg daily until abstinent >3 months (which may mean indefinitely). Thiamine is given parenterally if the patient is unwell or receiving IV fluids, and parenteral treatment should always commence prior to IV glucose, as a carbohydrate load may precipitate Wernicke’s enecephalopathy. If there is any suggestion of confusion or WKS, thiamine should be given 100mg tds by IVI or IMI.
The chronic phase of the Wernicke-Korsakoff syndrome, Korsakoff’s psychosis, is dense anterograde amnesia with confabulation, apathy and gross functional impairment, reflecting damage to the anterior nucleus of thalamus. Estimated prevalence is 12% in alcoholics, so it is still common. It may overlap with features of alcohol-related cerebrocortical degeneration, including frontal lobe syndrome (with impaired abstract thinking and executive function, disinhibition and personality change) and pre-senile dementia.
Diagnosis requires a history of harmful alcohol use, and exclusion of other explanations for symptoms (eg diazepam use). Bed-side tests of cognition like the Mini Mental State Examination are usually sufficient, however MMSE is not sensitive to early disease (Manning et al 2007). The Clock test is moderately sensitive and specific and very quick and very cheap! (Pinto and Peters Dement Geriatr Cogn Disord. 2009 27(3):201-13). Formal neuropsychiatric testing is useful to determine functional capacity and in doubtful cases, but is costly, time consuming and difficult to do in this population. Dr Haber considers it is over-ordered.
The etiology of alcohol-related cerebellar damage, like Wernicke’s, has a nutritional component, and these syndromes may overlap, or even form a continuum; but unlike Wernicke’s, cerebellar damage evolves subacutely over months & is often not fully reversible. Characteristically, there are wide-based stance and gait, with the legs worse affected than the than arms, while speech and ocular movements are relatively spared. The cerebellum also involved in perception and executive functions and memory, so cerebellar damage may contribute to cognitive deficits. Treatment involves alcohol abstinence, thiamine and multivitamins.
Alcohol is associated with stroke by a J-shaped curve, like cardiovascular disease. Moderate consumption lowers stroke risk but there is 4-5 times increased risk at high levels of consumption. Heavy drinking is associated with smoking and with hypertension. Brain haemorrhage (arachnoid, intracranial and subdural) needs to be considered in any confused or obtunded person with a history of harmful alcohol use. A rare but important alcohol-related problem is central pontine myelinolysis, causing quadriparesis and locked in syndrome, when hyponatremia is too rapidly corrected. Diagnosis is confirmed by MRI.
Finally, an estimated 50-75% of traumatic brain injury is associated with substance use, but 50% of cases do not present to hospital, and previous brain injury is often overlooked in clinical history and examination. Alcohol use is associated with poorer prognosis and delayed recovery from brain injury which in turn is associated with poor outcomes of alcohol treatment.
Indeed, most “talking therapy” is cognitively intensive and may be beyond the capacity of people with alcohol-related brain damage, in terms of reasoning skills, attention skills and memory. One needs either to adapt the program or discontinue it. Rehabilitation services present a particular challenge: the patient who most needs this treatment is least likely to benefit from it.
CASE STUDIES:
In the second half, three Case Studies of the Bach Siblings were worked through, to show the need to consider a range of causes for collapse, confusion, and ataxia in heavy drinkers.
Wilhelm Friedrich Bach, a 58 year old male disability pensioner was brought in to the Emergency Department by ambulance, hypothermic (oral temperature 34) after being found lying supine on the footpath in an inner city street, smelling of alcohol. He had been drinking daily since the age of 25.
He was conscious with no neurological deficit but had a deep laceration to his scalp. There were marked hepatomegaly and epigastric tenderness. Haemoglobin was 94 and WBC 13.9 x 109/L. LFTs were consistent with alcoholic hepatitis. Coagulation parameters were normal. Cerebral CT was reported normal.
Hypotheses for his collapse included alcohol intoxication, sepsis, myocardial infarction, gastrointestinal bleeding, head injury, seizure, other drug use ….
Oral thiamine 100mg bd and alcohol withdrawal scale (AWS) were started, reaching a maximum 7 on the 3rd day of admission. Oral diazepam was given, totalling 20mg, 30mg and 60mg on the first 3 days. On the 4th day the patient showed flat affect, slow speech and had a gross tremor of both hands, and a wide-based ataxic gait. Mini Mental State Examination score was 24/30. The patient was disoriented in time and place with poor performance evident in short term recall, abstract thinking and construction.
The differential diagnosis of his ataxia and confusion included cerebellar disease, Wernicke’s and alcohol-related cerebrocortical damage. Review of his cerebral CT showed global atrophy, suggesting the possibility of repeated traumatic injury in the past.
2 weeks after admission, his activities of daily living had improved to the point where he was considered suitable for placement in the rehabilitation hostel level.
His younger brother, Carl Philip Emmanuel Bach, a 46 year old male on sickness benefits, was brought in by ambulance with a 3 day history of being essentially bed-bound; unable to walk, he had been crawling to the bathroom and showered sitting on the floor. He was currently drinking about 300g-400g alcohol/day, and had been admitted to hospital on several occasions for alcohol withdrawal-related seizures.
Hypotheses for his inability to walk included cerebellar disease, Wernicke’s and alcohol-and malnutrition-related muscle wasting.
On examination, he had profound truncal and gait ataxia, pronounced scanning dystharthria, and symmetrical vertical and horizontal nystagmus; dysmetria (finger-nose past-pointing), dysdiadochokinesia and heel-shin ataxia. Limb muscle power, tone and reflexes were normal but there were diminished light touch sensation in the hands, and diminished light touch and pin-prick sensation and proprioception in the feet.
Investigations: he had negative serology for HIV, and screen for a range of neuronal antibodies was negative; cerebral CT was reported as showing generalised cerebral and cerebellar atrophy. There was no enhancement of the mamillary bodies with contrast (a radiological sign of necrosis at this site in Wernicke's disease). Electromyogram was consistent with moderate-severe peripheral neuropathy.
The diagnosis of alcoholic cerebellar degeneration, with severe midline and lateral cerebellar dysfunction, was made. After 4 months in the rehabilitation ward, he remained unsafe walking even with support, and hostel accommodation was required.
Ms PDQ Bach, 52 years old, was brought in by ambulance after falling down the stairs at home. She had been drinking daily since the age of 30. She had previously worked as an auditor but had been unable to work for the previous 4 years; she had been lately prone to leaving the house for a walk with the doors and windows wide open and no-one at home.
She was conscious and oriented with a Glasgow Coma Scale score of 16. There were marked hepatomegaly and cerebellar ataxia. She was incontinent of urine and faeces. LFTs showed alcoholic hepatitis. Cervical spine and cerebral CTs were normal.
The hypotheses for her fall were similar to those for her elder brother. She too was given oral thiamine 100mg and an alcohol withdrawal scale (AWS) was commenced, The AWS peaked at 6 on the 3rd day, and a total of 50mg of diazepam was given on this day, 60mg on the fourth day and the final AWS-determined dose of diazepam at lunch time on day 5, however PRN diazepam continued.
On the 6th day, PDQ’s gait remained unsteady and shuffling and she was mildly disoriented and belligerent, with a MMSE score of 23. She did not see why she should stay in hospital, though she could not walk safely, and was still incontinent of urine.
Hypotheses for her mental state included Wernicke’s, alcohol-related cerebrocortical damage, and the effects of continuing diazepam.
On the 15th day, the patient attempted to leave the hospital, wandering, confused, disoriented, paranoid and agitated. On psychiatric assessment, she was determined to have no perceptual disturbances or evidence of paranoia, but evidence of confabulation. The Mini Mental State Examination score was 21/30 with poor registration and recall, abstract thinking, sentence repetition and design. She was treated with haloperidol 5mg orally, and risperidone to begin 0.5mg orally bd; a 24 hour attendant was arranged under 'duty of care' provisions.
Formal neuropsychiatric testing later showed impaired cognition, delayed information recall with inclusion of intrusive and incorrect information, slow psychomotor function, including slow page scanning; reduced awareness and insight; deficits in cognitive and semantic fluency, visuo-spacial and visuo-constructional skills. These were said to be all consistent with alcoholic brain damage: further the memory problems were considered consistent with Korsakoff's syndrome.
Nine weeks after admission, the patient was still awaiting suitable placement.
In each of these cases, Dr Haber suggested thiamine should ideally have been given parenterally in the emergency department, rather than orally.
Written by Richard Hallinan FAChAM based on talk and power point presentation by Prof Paul Haber on Tuesday 20th April 2010 at Concord Hospital as part of the Concord Dependency Seminar Series. http://dependencyseminars.blogspot.com/
