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Case PresentationUpdate on controversies and researchCase PresentationUpdate on controversies and research
Alex Mitchell & Nasser Abdelmawla
alex.mitchell@leicspart.nhs.ukalex.mitchell@leicspart.nhs.uk Neuropsychiatry Meeting 23 August 2005Neuropsychiatry Meeting 23 August 2005
• HistoryDid Wernicke and Korsakoff recognise both presentations?
• Clinical FeaturesIs there a characteristic triad to Wernicke’s syndrome?Is amnesia focal in Korsakoff’s syndrome?
• Pathology & PathophysiologyWhere is the lesion?What is the role of direct alcohol neurotoxicity?
• TreatmentIs treatment entirely symptomatic?
Karl Wernicke (1848-1905)
German neurologist and psychiatrist, born May 15, 1848, Tarnowskie Gory, Poland; died June 15, 1905,
K. Wernicke K (1881) Die acute, hämorrhagische Polioencephalitissuperior. Lehrbuch der Gehirnkrankheiten; Kassel, Fischer, and Berlin, 1881, 22: 229-242.
In 1881 a young woman was admitted to a hospital after having swallowed a substantial amount of sulphuric acid. Over 4 weeks she developed photophobia, an impairment of vision, drowsiness and a stumbling gait. Upon examination, convergent strabismus, paralysis of the bilateral abducens, impairment of horizontal gaze and vertical nystagmus on upward gaze was noted. Her mental condition showed intermittent somnolence, disorientation, apathy, nocturnal restlessness and fright. The symptoms progressively worsened and she died within a fortnight of their onset.
In the same year, Wernicke saw similar symptoms in two alcoholic men, both having been hospitalised in a delirious state. In one, ataxia of gait and diplopia (bilateral abducens paralysis) had preceded the delirium, whereas, in the other, ataxia, ophthalmoplegia, redness of the optic discs, and an isolated retinal haemorrhage became apparent after subsidence of the delirium. Both patients died after a short period of somnolence and stupor. He named the syndrome haemorrhagic polioencephalitis
Sergei Sergeievich Korsakoff
Russian neuropsychiatrist, born January 22, 1853, Gus estate, Vladimirsk; died May 1, Moscow, 1900.
Six years after the description of Wernicke's disease, SS Korsakoff (1853-1900) gave the first comprehensive description of the unique amnesic syndrome that is now known as Korsakoff's Psychosis.
In 1887 and again in 1890 he drew attention to several cases of alcoholic polyneuritis with distinctive mental symptoms. “This mental disorder,” he said, “appears at times in the form of sharply delineated irritable weakness in the mental sphere, at times in the form of confusion with characteristic mistakes in orientation for place, time and situation, and at times as an almost pure form of acute amnesia, where the recent memory is well preserved . . . . Some have suffered so widespread a memory loss that they literally forget everything immediately.”
He called the disease “syndrome psychosis polyneuritica”
WK Frequency – Autopsy BasedWK Frequency – Autopsy BasedNew York (Cravioto , 1961) [12] 28/1600 1,7%
New York (Rimalovski, 1966) 138/4000 3,5%
Cleveland (Victor, 1971) 77/3548 2,2%
Perth (Harper, 1979) [10] 51/2891 1,7%
Perth (Harper, 1983) 131/4677 2,8%
Oslo (Torvik, 1982) 70/8735 0,8%
Sydney (Harper, 1989) 6/ 285 2,1%
Classical Clinical Features - WKClassical Clinical Features - WK
• 1. Ocular abnormalities
• 2. Ataxia
• 3. Cognition
• Other Features
Hypothermia if hypothalamic involvementPeripheral neuropathy (is this the cause of the ataxia?)Cardiovascular dysfunction may be observed. –Postural hypotension, Tachycardia, SyncopeOvert signs of beriberi heart disease are rare
Classical Clinical FeaturesClassical Clinical Features
• Ocular abnormalities: can occur singly or in combination Nystagmus, vertical and horizontal Paralysis of lateral rectus (occurs bilaterally but can be asymmetric and
is accompanied by diplopia and internal strabismus) Weakness or paralysis of conjugate gaze Non-reacting miotic pupilsPtosis, small retinal hemorrhagesoptic neuropathy (occasionally) Rarely Papilledema (very rare)
• Ataxia is manifested as an abnormality of both stance and gait. Vestibular paresis also plays a role in ataxia in the early stages of disease. Mildest form evident on tandem walking only Wide-based stance Slow and uncertain short-stepped gait Abnormal results on caloric testing (indicates vestibular paresis)
Classical Clinical FeaturesClassical Clinical Features
• CognitionGeneral disorientationOften delirium
The Korsakoff state is characterized by both anterograde (ie, learning) and retrograde (ie, memory of past events) amnesia.
Gaps in memory lead to => confabulation.
• Stupor or coma can be observed in more severe cases but is rare as an initial presentation.
Classical Clinical Features – Victor & AdamsClassical Clinical Features – Victor & Adams
Presenting symptoms in 163 patients
N %Confusion 108 66
Memory loss 33 20
Staggering gait 84 51
Ocular (”staring”, ”cross-eyed”, etc) 65 40
Polyneuropathy 59 36
”Collapse”, ”exhaustion” 33 20”Bedridden” 40 25
Alcohol withdrawal symptoms 21 13Other 25 15
Classical Clinical Features – Victor & AdamsClassical Clinical Features – Victor & Adams
Mental and behavioral abnormalities in 229 patients at initial examination
N %
Stupor 9 4
Coma 2 1
Alcohol abstinence syndrome 36 16
Global confusional syndrome 128 56
Disorder of memory* 131 57
No mental abnormalities 23 10
Symptoms in Those with Wernicke LesionsSymptoms in Those with Wernicke Lesions
Gade 1983Gade 1983
Diagnostic ErrorDiagnostic Error
• ”... The most striking finding in our material was that only 1 of 22 cases with active disease was diagnosed clinically”
Torvik et al., 1982
• Clinical diagnosis made in 16% of autopsy confirmed casesHarper et al MJA 1998; 168: 542-545
Prevalence of Wernicke-Korsakoff syndrome in Australia: has thiamine fortification made a difference?
Possible CausesPossible Causes
• Chronic alcoholism • Persistent emesis • Hyperemesis gravidarum• Gastric malignancy • Intestinal obstruction • Systemic diseases • Malignancy • Disseminated tuberculosis • Acquired immunodeficiency syndrome • Uremia/Chronichemodialysis• Starvation/Refeedingafter starvation • Anorexia nervosa • Iatrogenic • Intravenous hyperalimentation
Wernicke’s FindingsWernicke’s Findings
• Wernicke detected punctate hemorrhages affecting the graymatter around the third and fourth ventricles and aqueduct of Sylvius. He felt these to be inflammatory and therefore named the disease polioencephalitis hemorrhagica superioris.
• In addition there was inflammation, demyelination
Para-olfactoryarea
Hypothalamus
Uncus
AmygdalaPara-hippocampalgyrus
Hippocampus
Mamillary bodies ofhypothalamus
Fornix
Thalamus
Cingulate gyrus Anterior nucleus of thalamus
After Gade 1983
Charness & DeLaPaz, 1987
Harper & Matsumoto (2005) [% of control]Harper & Matsumoto (2005) [% of control]
Harding et al Brain (2000), 123, 141–154
Harding et al Brain (2000), 123, 141–154
Recent Functional Imaging?Recent Functional Imaging?
Reed (2003) FDG-PET findings in the WKS. CortexReed (2003) FDG-PET findings in the WKS. Cortex
KS = 12 vs 10 controlsrelative hypermetabolism in white matter and
medial temporal and retrosplenialhypometabolism in subcortical grey matter in Korsakoff patients.
Caulo et al Brain (2005) 128, 1584–1594Caulo et al Brain (2005) 128, 1584–1594
SPECT Correlates of AmnesiaJover et al Rev Neurol. 2004 Sep 16-30;39(6):597-8
SPECT Correlates of AmnesiaJover et al Rev Neurol. 2004 Sep 16-30;39(6):597-8
Thiamine and Cell DeathThiamine and Cell Death
ThiamineThiamine
1934 Prickett described pathological
changes in the brainstem of Vitamin B deficient rats.
1938 Alexander et al demonstrated
lesions in thiamine deficient pigeons and made link with WKS
1947 De Wardener and Lennox (1947)
described the occurrence of Wernicke Disease in 52 nutritionally deprived prisoners of war, of whom 32 had also developed a loss of memory.
Essential TreatmentEssential Treatment
• Wernickes is a medical emergency.
• Intravenous thiamine (50-100 mg) is the treatment of choice.
• Mg, K supplements (often low in people with alcoholism). –Also, Mg is a necessary cofactor in thiamine-dependent metabolism.
•
• Administration of intravenous glucose to patients who are severely malnourished can exhaust their supply of thiamine and precipitate Wernicke-Korsakoff syndrome.
Experimental TreatmentsExperimental Treatments
• McEntee et al (1980) have demonstrated decreased levels of a metabolite ofnorepinephrine(3-methoxy-4-hydroxyphenolglycolor MHPG) in the CSF of some patients with Wernicke-Korsakoffsyndrome.
• Clonidine, an alpha-noradrenergic agonist, seemed to improve the memory disorder of their patients.
New Treatments – Acetylcholinesterase New Treatments – Acetylcholinesterase Cochrane M, Cochrane A, Jauhar P, et al.
Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome - Three further cases show response to donepezilALCOHOL ALCOHOLISM 40 (2): 151-154 MAR-APR 2005
Phillips BK, Ingram MV, Grammer GG Wernicke-Korsakoff syndrome and galantaminePSYCHOSOMATICS 45 (4): 366-368 JUL-AUG 2004
Iga J, Araki M, Ishimoto Y, et al. A case of Korsakoff syndrome improved by high doses of donepezilINT CLIN PSYCHOPHARM 17: S97-S98 Suppl. 2 AUG 2002
Casadevall-Codina T, Pascual-Millan LF, Fernandez-Turrado T, et al. Pharmacological treatment of Korsakoff's psychosis: A review of the literature and experience in two casesREV NEUROLOGIA 35 (4): 341-345 AUG 16 2002
Sahin HA, Gurvit IH, Bilgic B, et al. Therapeutic effects of an acetylcholinesterase inhibitor (Donepezil) on memory in Wernicke-Korsakoff's diseaseCLIN NEUROPHARMACOL 25 (1): 16-20 JAN-FEB 2002
Iga JI, Araki M, Ishimoto Y, et al. A case of Korsakoff's syndrome improved by high doses of donepezilALCOHOL ALCOHOLISM 36 (6): 553-555 NOV-DEC 2001
New Treatments – Acetylcholinesterase New Treatments – Acetylcholinesterase
• Author(s): Cochrane M; Cochrane A; Jauhar P; Ashton E Title: Acetylcholinesterase inhibitors for the treatment of Wernicke-Korsakoff syndrome - Three further cases show response to donepezilSource:
• ALCOHOL AND ALCOHOLISM 2005, Vol 40, Iss 2, pp 151-154 Language: English
• Abstract: Three patients diagnosed with Wernicke-Korsakoffsyndrome were treated with the acetylcholinesterase inhibitor, donepezil, for periods of 6 to 8 months. Cognitive testing [Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), Mini-mental state examination (MMSE), Clock drawing test and six item 2 min recall] and carer questionnaires [Informant Questionnaire (IQ Code), Neuropsychiatric inventory scale (NPI)] were performed at baseline, mid- and endpoint of the treatment period and post-discontinuation. Progressive partial improvement occurred in cognitive measurements through the treatment period, some of which was sustained after discontinuing donepezil. Carer questionnaires also indicated improvement. Confounding factors necessitate caution when attributing improvements to the medication, but these cases suggest that this option merits further investigation.
New Treatments – Acetylcholinesterase New Treatments – Acetylcholinesterase
• THERAPEUTIC EFFECTS OF AN ACETYLCHOLINESTERASE INHIBITOR (DONEPEZIL) ON MEMORY IN WERNICKE-KORSAKOFF’S DISEASE
• CLINICAL NEUROPHARMACOLOGY 2002, Vol 25, Iss 1, pp 16-20 Language: English
• Abstract: Wernicke-Korsakoff's disease (WKD) is cognitively an amnestic state resulting from strategic lesions in the limbic system and resulting from thiamine deficiency. Neurochemical deficits have been implicated in the pathophysiology of amnesia based on the pathologic observations that various brainstem and basal forebrain nuclei are also affected. Previous treatment attempts with serotoninergic, noradrenergic, and cholinergic drug, hake given controversial results, The objective of this study was to assess the effects of a cholinesterase inhibitor, donepezil. on memory. attention, and executive C functions in patients with nonalcoholic WKD. Seven patients who developed WKD after a hunger strike were included in this single. blind, placebo-controlled. one-ay, crossover study. The patients were administered donepezil during the first 30 days, and were administered placebo during the 1,following 30 days. Neuropsychological tests to evaluate herbal and visual memory, and attention and executive function were performed on days 0, 3 1, and 6 1, All patients completed both phases of the study. There were no statistically significant differences between the three evaluations, except For a difference between active treatment and the placebo phase during recall of the Rey-Osterrieth complex figure, which as in favor of the placebo phase. There were no significant changes in favor of the active treatment. Cholinergic treatment with the cholinesterase inhibitor donepezil doe,,, not seem to provide marked beneficial effects in patients with WKD in this small. descriptive Study.
PrognosisPrognosis
• WKS has a 10-20% mortality rate (in acute stages)
• In general, full recovery of ocular function occurs. Fine horizontal nystagmuscan persist in as many as 60% of cases.
• Approximately 40% of patients have complete recovery from ataxia.
• Of patients surviving Wernicke encephalopathy, 80% have Korsakoffpsychosis.
• Of patients with Korsakoff psychosis, 25% do not recover and require long-term institutionalization.
• Only about 20% eventually recover completely during long-term follow-up care.
• Only 20% of patients recover completely from amnestic deficit.
Neurological Complication of AlcoholNeurological Complication of Alcohol
• Acute alcohol intoxication• Alcohol dependency syndrome• Delirium tremens• Alcoholic hallucinosis• Alcohol-induced dementia• Alcohol-induced mood disorder• Alcohol-induced sleep disorder• Alcohol-induced sexual disorder• Wernicke–Korsakoff syndrome• Alcoholic pellagra• Cerebellar degeneration• Head injury due to alcohol• Hepatic encephalopathy• Marchiafava–Bignami disease• Central pontine myelinolysis• Peripheral neuropathy due to alcohol
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