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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