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Departments of Psychology and Neurology, University of Helsinki, Finland
Academic dissertation to be publicly discussed, by due permission of the
Faculty of Arts at the University of Helsinki
in auditorium 2, Meilahti Hospital, on the 12th of December, 1997, at 12 oclock
ISBN 952-10-0162-3 (HTML version)
Original thesis printed in: Tummavuoren Kirjapaino Oy, Vantaa, Finland, 1997. ISBN 952-90-9347-0
|Professor Veijo Virsu, Ph.D.
Department of Psychology
University of Helsinki, Finland
|Professor Matti Iivanainen, M.D.
Department of Child Neurology
University of Helsinki, Finland
|Docent Matti Laine, Ph.D.
Department of Psychology
University of Turku, Finland
|Docent Aarne Ylinen, M.D.
Department of Neurology
University of Kuopio, Finland
|Assistant Professor Juhani Vilkki, Ph.D.
Department of Psychology
University of Helsinki, Finland
LIST OF ORIGINAL PUBLICATIONS
This thesis is based on the following publications, which are referred to in the text by their Roman numerals I-V
I. Hokkanen L, Launes J, Vataja R, Valanne L and Iivanainen M. Isolated retrograde amnesia for autobiographical material associated with acute left temporal lobe encephalitis. Psychol Med 25, 203-208 (1995).
II. Hokkanen L, Salonen O and Launes J. Amnesia in acute herpetic and non-herpetic encephalitis. Arch Neurol 53, 972-978 (1996).
III. Hokkanen L, Launes J, Poutiainen E, Valanne L, Salonen O, Sirén J and Iivanainen M. Subcortical type cognitive impairment in herpes zoster encephalitis J Neurol 244,239-245 (1997).
IV. Hokkanen L and Launes J. Cognitive recovery instead of decline after acute encephalitis: a prospective follow up study. J Neurol Neurosurg Psychiatry 63, 222-227 (1997).
V. Hokkanen L and Launes, J. Duration of transient amnesia correlates with cognitive outcome in acute encephalitis. NeuroReport 8, 2721-2725 (1997).
In addition, some unpublished data are presented.
ANOVA analysis of variance
CNS central nervous system
CSF cerebro spinal fluid
CT computed tomography
HSV Herpes simplex virus 1
HSVE Herpes simplex virus 1 encephalitis
HZE Herpes zoster encephalitis
LTM long-term memory
MANOVA multiple analysis of variance
MRI magnetic resonance imaging
MQ memory quotient of the WMS
PIQ performance intelligence quotient of the WAIS
SPECT single photon emission computed tomography
STM short-term memory
TENA transient encephalitic amnesia
WAIS Wechsler adult intelligence Scale
VIQ verbal intelligence quotient of the WAIS
WMS Wechsler Memory Scale
VZV Varicella zoster virus
Neurological diseases that affect cognitive processes and memory include stroke, brain trauma, certain degenerative disorders, cerebral tumours and central nervous system (CNS) infections. Acute encephalitis is an inflammation of the brain parenchyma that is usually caused by viruses, although bacterial, other microbial and post-infectious forms are also known. In the USA, 20 000 cases occur each year (Hanley et al. 1987). In Finland, the incidence of meningoencephalitis and encephalitis is thought to range from 2 to 3.5 cases per 100,000 inhabitants, that is, from 100 to 175 cases, annually (Klemola et al. 1965; Palo et al. 1984; Mäkelä et al. 1993).
Symptoms at the acute stage often include fever, fatigue, alteration of consciousness, disorientation and memory defects. The patient may recover within a few days, or it may take months for the acute symptoms to subside. A variety of cognitive deficits may persist after the acute stage, and they are often the sole cause of disability and retirement, pareses and other neurological sequelae being relatively rare. Disorders of memory are particularly prominent. Certain viruses cause damage to the temporal and fronto-basal areas, resulting in a pure amnestic syndrome. In other encephalitides, the site of lesion is less selective, but variable memory deficits are the most commonly reported sequelae.
Neuropsychological assessment is crucial in the evaluation of the outcome of patients with encephalitis. Impairments in thought processes, memory, speech and perception can be evaluated with the aid of neuropsychological tests. As a speciality, neuropsychology lies at the crossroads between neurology, neuropsychiatry and cognitive psychology, and is closely intertwined with the current developments in neuroscience.
Because of the high frequency of memory complaints following encephalitis, the aim of this study was to investigate different types of memory impairment at the acute stage of encephalitis and during follow-up using the methods of clinical neuropsychology.
2. Review of the literature
2.1 Human memory
Different memory systems
Human memory is usually divided into stages comprising the encoding or registering, storing, and accessing or retrieving of information (Baddeley 1995; Lezak 1995). Further classification systems may be based on the time span of memory processing, the level of processing, the subjects consciousness of the learning event, the modality through which the material is presented or the content of the material. Among the first analytical theories of memory processes was the Modal Model (Atkinson and Shiffrin 1968). Registration occurs in sensory memory stores, which briefly (time span of milliseconds) attend to incoming stimuli of different modalities (iconic, echoic or haptic memory). The environment may be monitored unintentionally, as has been demonstrated within the auditory sensory memory system (the mismatch negativity pattern (Näätänen 1990)). Storage is achieved by two successive, and interactive, systems: short-term memory (STM) and long-term memory (LTM).
Cognitive models of working memory
Immediate memory, sometimes labelled the first stage of STM, can hold 5-9 chunks of information for a period of a few seconds (Vallar and Papagno 1995). This system was earlier called primary memory. Rehearsal, as well as other processes that enable consolidation of information into the LTM, also takes place in the STM. Alan Baddeley has proposed a concept of working memory that comprises two parallel coding systems: a visuo-spatial sketch pad and a phonological/articulatory loop, which serve as short-term stores of visuo-spatial and acoustic information, respectively (Baddeley 1976; Baddeley 1986; Baddeley 1995). In his model Baddeley includes a controlling attentional system, the Central Executive, which supervises and co-ordinates the two slave systems (Baddeley 1997). A similar controlling system has been suggested by Norman and Shallice (see Shallice 1982): the Supervisory Attentional System is called into play when specialised routine programmes (schemas) are inadequate, and intentional processes and planning are needed to perform a task. The working memory model has been expanded by J.Jonides, who suggests two separate systems for analysing visual and spatial information in addition to the phonological store (Jonides 1995). He even elaborates further to hypothesise a modality-free coding system for storing information in terms of its conceptual properties (Jonides 1995).
The LTM, or secondary memory as it used to be known, can also be divided into several subsystems. Implicit memory refers to learning without a recollection of learning. This type of learning has also been labelled procedural or non-declarative, depending on the exact nature of the task. Different types of nondeclarative memory include skills and habits, priming effect and conditioning. Declarative, or explicit, memory includes both a semantic memory system, which is the store for facts and knowledge categories, and an episodic memory system, which is the store for personally experienced episodes or events which are time and place specific (Tulving 1972).
It has earlier been argued that learning occurs through accumulation of episodic memory traces, which eventually "crystallise" into a semantic knowledge base loosing their context specificity (Cermak 1984). The hierarchy or interaction between the two systems is currently under debate (Verfaellie 1997). New insights into the semantic system have accumulated as a result of studies on the degenerative condition semantic dementia (Snowden et al. 1989). Patients with semantic dementia show a pattern of preserved recent memories and impaired distant memories, whereas patients with Alzheimers disease or other types of amnesia typically show temporally graded memory loss (poor recall of recent memories) (Graham and Hodges 1997). It has now been proposed that episodic and semantic memory systems are in constant bi-directional relationship, memories of episodes in the past having a "semantic" character, and memories of contemporary semantic facts having an "episodic" or autobiographic character (Snowden et al. 1996).
All the above memory processes can be termed retrospective in the sense that they store data accumulated in the past. Prospective memory, the capacity to remember - or anticipate - things that will happen in the future, has also been identified (Baddeley 1997).
Memory failure can occur through several mechanisms, of which only a few are known to date (see Shimamura 1989; Baddeley 1997). Encoding may be faulty due to sensory defects, but also due to attentional deficits or superficial processing. According to one input theory, amnesic patients do not spontaneously encode material at a deep semantic level, and therefore learning is incomplete. A decrease in processing speed may also deter consolidation and storage (Salthouse 1996). Retrieval may be inhibited by disorganised access strategies. Amnesic patients may be poor at associating what they have learned with the cues necessary for retrieval. Forgetting can be explained by spontaneous fading of memory traces or by interference from other memory items (Baddeley 1995). The variety of subsystems that can fail may explain the variability in memory impairments.
2.1.2 Neurobiological correlates of human memory
The biology of memory can be studied at several levels. The molecular bases of memory have been the target of active research in recent years, and several breakthroughs have been made in the investigation of memory-related neurotransmitters, such as acetylcholine and glutamate (Tranel and Damasio 1995). At the cellular level a major breakthrough was the observation of long-term potentiation (LTP) in hippocampal cells (Bliss and Lomo 1973). Through LTP the excitability of a postsynaptic cell remains increased for hours or days after an adjacent presynaptic cell has been stimulated. The increased excitability seems to occur only in some synapses of the presynaptic cell, and therefore potentiation acts in producing specific and meaningful circuits (Bliss and Collingridge 1993). A weak synaptic connection may also be strengthened by a simultaneously occurring strong activation nearby. LTP has been suggested to be involved particularly in associative learning (Doyère et al. 1993).
The role of the hippocampal complex in memory systems has been emphasised since the description of a classic case of amnesia, H.M. (Scoville and Milner 1957). The medial temporal lobe contains several structures, that is, the hippocampus, the amygdala, the entorhinal and perirhinal cortices and the parahippocampal gyrus, which are critical for declarative, anterograde memory. The principal function of the hippocampal complex is thought to be the acquisition of new knowledge of events and facts (Squire and Zola Morgan 1991; Tranel and Damasio 1995). In normal subjects, studied with functional MRI (fMRI), encoding tasks have yielded increased signals for unfamiliar information in a posterior medial-temporal region, particularly in parahippocampal cortex, whereas retrieval tasks have yielded increased signals for successfully remembered information in an anterior medial-temporal region, particularly in the subiculum (Gabrieli et al. 1997). Retrograde - or remote - memory seems to be more independent of the hippocampal complex. Nonmedial temporal structures, that is, anterior, inferior and lateral portions of the temporal lobe, are involved in the retrieval of previously learned knowledge (Squire and Zola Morgan 1991; McClelland et al. 1995; Tranel and Damasio 1995; Garrard et al. 1997).
Thalamus and related diencephalic structures, such as mamillary bodies, have been associated with memory processes ever since the neuroanatomical correlates of the Wernicke-Korsakoff syndrome were found (Adams 1969). Penetrating brain injuries affecting diencephalic regions, such as a fencing foil accident in patient N.A. (Teuber et al. 1968) or war injuries reported in Finland (Jarho 1973), have been found to result in a similar type of amnesia. More recently, thalamic strokes have been implicated in producing memory deficits (Bugousslavsky et al. 1988; Ghidoni et al. 1989).
There are also several memory-related neural systems in the frontal lobes. Ventromedial regions seem to play a role in prospective memory, while the dorsolateral region may be involved in estimating the frequency or recency of an event (Shimamura et al. 1991; Tranel and Damasio 1995). Frontal dysfunction may lead to impaired memory performance also because of deficits in attentional processes (Vilkki 1989), or because of increased perseverative tendencies (Vilkki and Holst 1989).
New methods for studying normal, healthy subjects - such as positron emission tomography (PET), the refined measurement of event-related potentials (ERPs), as well as fMRI - have greatly influenced the memory research. The improved imaging techniques have revealed that both sensory neocortices - or the primary association areas for visual, auditory and somatosensory information - and the secondary areas of visuospatial integration become active in memory processing (see Rösler et al. 1995; Ungerleider 1995; Cabeza and Nyberg 1997). Similarly, memory of learned motor sequences have been found to involve the same sites that control limb movement (Grafton et al. 1992). Basal ganglia and the cerebellum have also been linked to various forms of nondeclarative, procedural, memory, that are dependent upon motor functions (Tranel and Damasio 1995). It appears that the same association cortices that are called into service when information is perceived are used when that information is later recalled (Tranel and Damasio 1995).
Figure 1 shows a schematic presentation
of various forms of memory processes and their neuroanatomical correlates
(Squire and Knowlton 1995; Ylinen and Sirviö 1997). Nearly all parts
of the brain are today thought to be involved in different memory processes.
Memory performance is therefore affected, in one way or another, in most
diseases of the nervous system.
2.1.3 Clinical amnesic subtypes
In behavioural neurology, organic amnesias can be classified as transient or permanent (see Figure 2). Epilepsy, electro-convulsive therapy and brain trauma are known to result in transient amnesia. This type of memory loss refers to a global disturbance of continuous day-to-day memory. During amnesia, patients are disoriented and unable to form memory traces of ongoing events. The cause of the transient global amnesia syndrome is as yet uncertain, but single photon emission computed tomography (SPECT) studies have revealed hypoperfusion bilaterally in postero-medial temporal lobes (Tanabe et al. 1991; Evans et al. 1993) and the thalamus (Goldenberg et al. 1991) during the attack. The length of post-traumatic amnesia (PTA) after traumatic head injury has been used as an indicator of the severity of brain injury and a predictor of outcome (Russell and Smith 1961; Dikmen et al. 1987).
The most commonly agreed features of the amnesic syndrome are normal intelligence, normal attention span, a severe and permanent learning deficit (anterograde amnesia), loss of memory of information predating the onset of the brain damage (retrograde amnesia) and preserved skill acquisition (Parkin 1984; Parkin and Leng 1993; O'Connor et al. 1995). Amnesia in diencephalic abnormalities (e.g. Wernicke-Korsakoff syndrome, thalamic infarcts and tumours of the third ventricle), amnesia in medial temporal and hippocampal brain lesions (surgical ablation and anoxia) and memory impairment after lesions leading to frontal dysfunction have been described as subtypes of amnesia (Parkin 1984; Parkin and Leng 1993; O'Connor et al. 1995).
Features of the memory impairment that follows medial temporal lobe lesions are described to be preserved insight, no confabulation, limited retrograde amnesia and tendencies towards rapid forgetting, whereas patients with damage to the diencephalon are depicted as having confabulatory tendencies, diminished insight and extensive and temporally graded retrograde amnesia. Memory impairment following frontal system lesions is characterised by relative preservation of recognition versus deficient free recall, deficits in tasks of contextual memory and impaired semantic categorisation.
Despite general acceptance of this classification, the issue of amnesic subtypes is controversial. The neuroanatomical distinction between medial temporal and diencephalic groups is not clear-cut, and common neuropathology (e.g. mamillary body damage) may be present in all forms of amnesia. Furthermore, disconnection of a certain structure from adjacent areas may produce symptoms similar to those that follow a lesion in the structure itself. It has also been suggested that post-encephalitic amnesia (especially in Herpes simplex encephalitis, HSVE) might differ from other temporal lobe amnesias in that frontal pathology contributes to the cognitive disorders (Parkin 1984).
2.2. Neurological outcome in various encephalitides
The aetiology of encephalitis is often difficult to determine, and one to two thirds of cases lack microbial specification. Some of the most important viral causes of acute encephalitis are listed in Table 1. Table 2 presents the most common causes and outcomes as recorded in epidemiological studies of encephalitis conducted in the USA, UK, Germany and Finland. The frequency of residual neurological disability after acute encephalitis has been from 10 to 30% but no distinction between cognitive and other symptoms was made in these studies. Aphasia, mental deterioration, "organic psychosyndrome", epilepsy, dysarthria, ataxia and hemiparesis have all been reported (Meyer et al. 1960; Miller and Ross 1968; Kennard and Swash 1981; Buttner and Dorndorf 1988). Improvements in antimicrobial medication and neurointensive care have probably improved the prognosis of patients with encephalitis during the past decade.
2.2.1. Herpes virus group
Eight different herpes virus types affecting humans are currently known (Mäkelä et al. 1993; Moore et al. 1996): Herpes simplex virus -1 (HSV), Herpes simplex virus -2 (HSV2), Varicella zoster virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV) and Human herpes viruses 6-8 (HHV6, HHV7 and HHV8). All exhibit a characteristic tendency to produce latent infections, the virus remaining silent in the host for years, with sudden activation in response to a variety of stimuli (ultraviolet light, hormonal factors, mental stress, other infections etc.). Encephalitis is a known complication in all herpes virus infections, with the exception of HHV7 and HHV8, in which no clinical correlation has yet been found.
Herpes simplex 1
In the Western world, sporadic viral infections account for the majority of cases, and the most common single aetiology is Herpes simplex 1-virus (Wood and Anderson 1988). In the USA the estimated incidence of HSVE is 0.5-1 per 250,000 persons per year (Whitley 1990) and in Sweden at least 2.3 cases per million inhabitants per year (Sköldenberg et al. 1984). Antibodies to HSV as a result of a childhood infection have been found in about 85% of the adult population (Mäkelä et al. 1993).
The virus is known to remain latent predominantly in the trigeminal ganglia and, once activated, to result in the typical labial lesion known as "the cold sore". At times it also spreads via tentorial branches of the trigeminal nerve up to the brain (Davis and Johnson 1979) where it causes various CNS infections such as meningitis and polyradiculomyelitis as well as encephalitis (Olson et al. 1967; Färkkilä et al. 1993). HSV causes a number of different neuropathological findings, but focal necrosis in the medial temporal lobes, hippocampal complex and basal forebrain (Hierons et al. 1978; Kapur et al. 1994; Yoneda et al. 1994) is considered the most typical. The proximity of these regions to the meninges in the basis of the middle fossa, which is innervated by the trigeminal nerve, is believed to explain the location of the lesions (Davis and Johnson 1979). It has also been suggested that the distinctive neuroanatomical, neurochemical and neuroimmmunological properties of these phylogenetically older areas might explain the selective destruction of the limbic system (Damasio and Van Hoesen 1985). The damage caused by the encephalitis has been found to progress months after the acute stage in patients not treated with acyclovir (Enzmann et al. 1978; Koskiniemi and Ketonen 1981).
Common signs of HSVE are seizures, fever, headache, mental abnormalities and aphasia (Olson et al. 1967; Oxbury and MacCallum 1973; Whitley et al. 1982). The outcome has been poor with mortality of up to 75% (Olson et al. 1967; Whitley et al. 1977; Huber et al. 1989) and severe disability and dependency in survivors (Oxbury and MacCallum 1973; Kennedy 1988). Personality change, motor deficits, aphasia, dementia, amnesic syndrome and epilepsy have been reported as residual symptoms (Olson et al. 1967; Oxbury and MacCallum 1973). Reports of mild forms of HSVE have been few, but in one study three patients with HSVE established by biopsy were said to have recovered fully without specific antiviral therapy (Klapper et al. 1984).
Acyclovir treatment has altered the prognosis of HSVE. The mortality in an acyclovir-treated group decreased to 19% compared with 50% with other treatments (Sköldenberg et al. 1984; Whitley et al. 1986). Severe impairment (=continuous need for care) occurred in 18-42% of survivors and moderate impairment in 12-14% (=patient returned to gainful employment but did not function at the previous level); mild or no sequelae were found in 46-68% of the patients (Sköldenberg et al. 1984; Whitley et al. 1986). Age, level of consciousness at the onset of therapy, and disease duration before the onset of therapy predict the outcome (Whitley et al. 1987). Specifically, if treatment is initiated within four days of the onset of symptoms, the prognosis may be more favourable (Whitley et al. 1987; Jouanny et al. 1994; Marton et al. 1996) than in cases in which there are longer delays.
Herpes simplex 2
HSV2 virus remains latent in the sacral ganglia, and the recurrent infections typically result in genital lesions. The reasons for the differences in the pathogenesis of Herpes simplex types 1 and 2 are unknown (Whitley 1990). HSV2 is known to induce recurrent meningitis more often than encephalitis. Of the five reported cases of HSV2 encephalitis (Morrison et al. 1974; Sutton et al. 1974; Linnemann, Jr. et al. 1976; Young et al. 1976; Oommen et al. 1982), the outcome was fatal in three, recovery was complete in one case and partial in one case. The latter case complained of transient episodes of dizziness and moderately severe memory loss after discharge (Young et al. 1976).
Varicella zoster virus
VZV is the cause of both varicellae (chickenpox) and herpes zoster (shingles); the occurring illness depends on the immunological status of the individual. Encephalitis occurs in up to 5% of patients hospitalised because of herpes zoster (Mazur and Dolin 1978) and in less than 0.05% of adult patients hospitalised because of varicellae (Guess et al. 1986). Here the term herpes zoster encephalitis (HZE) is used for both conditions. In adults, VZV is found to reside latent in the trigeminal and thoracic ganglia (Mahalingam et al. 1992). VZV replicates in neurones, glial cells, fibroblasts, striated muscle, epidermal cells, sweat glands and blood vessels, and is thus able to infect a broad range of CNS cells (Schmidbauer et al. 1992). Both focal and diffuse cortical damage and subcortical pathology are therefore possible in HZE.
In reviewing the clinical and pathological outcome of 40 patients with zoster encephalomyelitis, Rose et al. (1964) noticed that mental functions were intact in only six (15%) patients (Rose et al. 1964). Patients were disoriented, confused and somnolent during the acute stage but their mental status improved during the following weeks. In an old series of varicella encephalitis, mortality was 10% and residual symptoms occurred in 16% of survivors (Miller et al. 1956). In two later series no deaths clearly attributable to varicella zoster virus were found, and all the patients were reported to have eventually returned to their prior cognitive status (Appelbaum et al. 1962; Jemsek et al. 1983). However, persisting cognitive symptoms such as memory impairment, dysphasia, difficulty in interpreting proverbs (Andiman et al. 1982; Reshef et al. 1985; Gjerstad et al. 1986) and, in some cases, dementia (Norris, Jr. et al. 1970) have been reported. The clinical course and outcome may be affected by the immunological status of the patient, and in immunosuppressed patients HZE may be more frequent and severe (Horten et al. 1981; Hughes et al. 1993). Treatment with acyclovir medication has had favourable results (Peterslund 1988).
Epstein-Barr virus and cytomegalovirus
Both EBV and CMV infect lymphocytes (Mäkelä et al. 1993). EBV primarily causes infectious mononucleosis in young adults, but variable neurological symptoms may either accompany the illness or be the only detectable clinical manifestation (Bernstein and Wolff 1950; Silverstein et al. 1972; Grose et al. 1975). The incidence of neurological involvement in mononucleosis has ranged from 0.4% to 26.5% (Silverstein et al. 1972), but in older adults encephalitis is a rare complication. The outcome is considered favourable, and in one review only two of fifteen patients suffered persisting paraparesis (Silverstein et al. 1972).
CNS complications of CMV infections are frequent in immunosuppressed patients (Vinters et al. 1989), but in immunocompetent adults only single cases have been reported (Pantoni et al. 1991; Studahl et al. 1992), some of them, however, fatal (Rousseau et al. 1993).
The arthropod-borne viruses, or arboviruses, are the most important cause of epidemic encephalitides world-wide. More than 500 identified viruses belong to this group, and about 60 of them infect humans (Mäkelä et al. 1993). Each geographic region of the world has its characteristic range of arboviruses, but they all are transmitted from host to host by arthropod vectors, such as mosquitoes or ticks. The arboviruses have been classified into three viral categories: togaviruses, flaviviruses and bunyaviruses, of which the latter two include viruses that cause encephalitis in Finland and other parts of northern Europe.
Japanese B encephalitis virus has produced serious epidemics affecting larger areas and more people in the world than any other encephalitic virus. The incidence has decreased markedly thanks to vaccination, but approximately 70 cases still occur each year in Japan (Shoji et al. 1990), and epidemics in China and India are not uncommon. The main CNS lesions appear in the thalamus, substantia nigra and Ammons horn (Weaver et al. 1958; Ishii et al. 1977; Shoji et al. 1990). The most important epidemic encephalitis in the USA is St. Louis encephalitis, in which focal lesions appear in the thalamus, substantia nigra and midbrain (Broun et al. 1958; Reyes et al. 1981; Monath et al. 1983). Both of these encephalitides can be fatal, and residual deficits in intellectual functions have long been known (Dickerson et al. 1952; Broun et al. 1958; Weaver et al. 1958).
Arboviruses in Europe cause two main clinical categories of tick-borne encephalitis (TBE). The Russian spring-summer encephalitis virus causes a severe disease, with a mortality of 30% and grave sequelae in half of the survivors. A milder form of meningoencephalitis occurs in mainland Europe and in Scandinavia (Frühsommer-meningoenzephalitis FSME or Zentraleuropäischen Zeckenenzephalitis). The type identified in Finland, Kumlinge virus, is carried by the Ixodes ricinus tick (Wahlberg et al. 1989).
Infection following the Scandinavian TBE virus has a biphasic course. At the viraemic stage, an influenza-like illness lasts for a few days. After a symptom-free period of 1-2 weeks, a second stage follows in about a quarter of the infected patients (Wood and Anderson 1988). Ataxia, tremor, central or peripheral pareses, pareses of the cranial nerves, speech defects and mental status changes may occur (Krech et al. 1969; Ackermann and Rehse Kupper 1979; Conrads and Plassmann 1982). The symptoms usually resolve in a month but one case of mild dementia has been reported (Ziebart-Schroth 1972).
Inkoo virus, which has been isolated from the common mosquito (Aedes) in Finland, usually results in a mild or subclinical infection. Encephalitis caused by Inkoo virus is a rare complication (Mäkelä et al. 1993).
Puumala virus, the cause of epidemic nephropathy (EN) or haemorrhagic fever with renal syndrome (HFRS), occurs in Finland and other parts of Europe. Mortality is much lower (0.2%) than in other HFRS diseases, e.g. Korean haemorrhagic fever, which is caused by Hantaan virus (mortality 10%), or the haemorrhagic fever caused by Seoul virus (mortality 2%) (Mäkelä et al. 1993). The original work describing EN (Lähdevirta 1971) includes one fatal case with encephalitis. Neurological symptoms are present in almost 100% of cases of EN but they may be due to toxic or metabolic factors. One case of EN encephalitis with the CNS possibly as the primary infection site has been reported (Launes and Hautanen 1988).
2.2.3. Other viral encephalitides
Influenza is an acute respiratory infection that spreads in epidemics. Complications commonly include bronchitis and pneumonia, and more seldom cardiac or CNS symptoms. Although rare, post-influenzal encephalitis has long been known in the literature. Reports of the epidemic of Influenza A infection in 1958 (Asian) mentioned neurological disorders in several cases. Of 16 serologically confirmed cases compiled from two reports, seven were fatal; seven patients recovered completely, and two were left with mild motor symptoms (Flewett and Hoult 1958; McConkey et al. 1958). Fatal cases have also been reported among children during later epidemics (Hochberg et al. 1975). A favourable outcome in adults has more recently been reported in encephalitis following both Influenza A (Sulkava et al. 1981) and Influenza B (Hawkins et al. 1987) infection. Patients returned to their previous occupations within a few months without evidence of residual deficit.
Adenoviruses are a common pathogenesis in upper respiratory and eye infections. At least 42 different serotypes are known (Mäkelä et al. 1993). CNS infection caused by members of the adenovirus group has been reported from time to time, mostly in children. Adult cases of adenovirus encephalitis are few and most of them have involved concomitant diseases. The outcome in adult patients is variable, both fatalities and complete recovery having been reported (Chou et al. 1973; Kelsey and McLean 1979; West et al. 1985). Amnesia over a period preceding hospitalisation has been noted in single cases (Wells 1971; West et al. 1985), but there are no studies of series. Intranuclear inclusion bodies and focal necrosis, as in HSVE, were found in one case of adenovirus encephalitis (Chou et al. 1973).
Measles, rubella and mumps viruses
Measles (Rubeola) is often accompanied by bacterial infections such as pneumonia. The most severe complication, however, is encephalitis, which occurs 1-3 weeks after the appearance of the rash. The incidence of encephalitis is around 1 per 1,000 cases of measles (Mäkelä et al. 1993) and it varies with age; only some 10% of all cases occur in adults (Miller et al. 1956). Although once considered only postinfectious, measles virus has been isolated from the brain (ter Meulen et al. 1972). In surveys conducted in the 1950s and 1960s mortality from measles encephalitis ranged from 15% to 25%. Half of the survivors recover fully but the other half suffered from various neurological and psychological sequelae (Miller et al. 1956; Croft 1969). A chronic condition, subacute sclerosing panencephalitis (SSPE), is also caused by measles virus, but it is clinically very different from acute encephalitis and, thanks to vaccination programmes, has been almost completely eradicated from the Western world.
Post-infectious encephalitis following rubella (German measles) has also been described. The incidence of encephalitic complications has been estimated to be 0.2 per 1,000 cases of rubella (Miller et al. 1956). In early surveys the mortality was around 20% and residual symptoms occurred in 8.5% of cases (Miller et al. 1956; Croft 1969). Today, rubella is considered a mild infection, although dangerous to the foetus. Adult cases of encephalitis following rubella have been reported only sporadically (Ikemura et al. 1984). Progressive rubella panencephalitis, which is distinct from the acute form, affects children with congenital rubella, although it may have a late onset with symptoms not appearing until the second decade (Townsend et al. 1976).
Mumps is another childhood disease in which meningoencephalitis may occur.
Before the development of the vaccination routine, mumps caused 10-15% of
all aseptic meningitides (Mäkelä et al. 1993). Reports of encephalitis
in adults are rare, but a form of chronic relapsing encephalitis was described
in an adult patient with a confirmed mumps infection in the CNS (Vaheri et
al. 1982). Mumps has not been reported to cause fatalities among adults in
recent years, and 77% of patients recover completely (Koskiniemi and Vaheri
Measles, rubella and mumps infections are rare in Finland today, due to the widespread use of the MPR vaccination.
2.2.4. Non-viral causes of acute encephalitis
Several bacteria are known to cause acute encephalitis, among them Rickettsia rickettsiae (Rocky Mountain spotted fever), Chlamydia psittaci and Chlamydia pneumonie. Mycoplasma pneumonie primarily causes pneumonia as well as milder respiratory infections. Neurological symptoms, including encephalitis and acute psychosis, are present in 0.1-7% of those infected (Sterner and Biberfeld 1969; Pönkä 1979). Encephalitis following Mycoplasma pneumonie infection may be either diffuse or focal, and the pathophysiology of CNS manifestation has been unknown (Koskiniemi 1993). Quite recently Mycoplasma pneumonie RNA was detected in the brain tissue of a patient with acute encephalitis (Launes et al. 1997a).
Borrelia burgdorferi infection may result in various CNS manifestations and cognitive deficits, although more often with insidious onset and chronic progression (Halperin et al. 1989; Pachner et al. 1989; Krupp et al. 1991).
The incidence of fungal diseases of the nervous system is low in Finland (Palo et al. 1984), although the current HIV epidemic may cause additional cases. The most common forms of fungal infections are aspergillosis, cryptococcosis, candidiosis and coccidioidomycosis. Cryptococcosis is usually caused by Cryptococcus neoformans, which has been found to infect lungs and the CNS with equal frequency (Lewis and Rabinovich 1972). The disease used to be fatal, but with modern medicines (amphotericin B and flucytosine) the prognosis has improved (de Wytt et al. 1982). Cryptococcosis in the CNS may present as meningitis or encephalitis (Lewis and Rabinovich 1972; Weenink and Bruyn 1978; de Wytt et al. 1982) and hydrocephalus often develops from meningeal scarring (Weenink and Bruyn 1978; Yu et al. 1988). Epilepsy as a residual symptom has been reported (de Wytt et al. 1982) although the recovery rate has been high.
A pathological differentiation can be made between diseases caused by direct invasion of infectious agents, and para- or postinfectious processes that may secondarily involve the brain (Johnson 1986; Griffin and Johnson 1990; Whitley 1990). In the latter case, the pathological changes result from an autoimmune or otherwise abnormal immunological reaction against, or triggered by, the infection and not from the direct effect of the infectious agent on the cell. This may lead to demyelination or vasculitis. In some cases the symptoms may be alleviated by immunosuppression. Some infectious agents, e.g. cholera and diphtheria, establish CNS reactions by releasing a neurotoxin. The pathological mechanisms of most infectious agents in the CNS are, however, poorly understood, and many of them may cause damage to the CNS by several mechanisms.
2.3.1. Clinical picture
The onset of acute encephalitis is often abrupt. Prodromal symptoms that precede CNS involvement may include non-specific flu-like symptoms such as fever, headache, vomiting, diarrhoea and fatigue. Personality change, inappropriate behaviour and psychotic episodes may also occur, and have been regarded as typical of HSVE. The symptoms may progress rapidly, with epileptic seizures and alteration of consciousness, even coma, occurring within hours. All epidemiological studies have reported abnormalities in thought processes, orientation and speech in the acute stage of encephalitis. A variety of disturbances of motor co-ordination, muscle weakness, spasticity and sensory changes may also occur. Focal motor or sensory signs may be more pronounced in HSVE than in other aetiologies, but the value of these findings in differential diagnostics is questionable (Whitley et al. 1982).
2.3.2. Confirmatory laboratory investigations
In acute encephalitis, the cerebrospinal fluid (CSF) is usually abnormal, and its leucocyte count is elevated. In acute viral infection, the exudative stage - which is the first of the succeeding stages in immunological reactions of the CNS - is short and therefore the cells that are seen tend to be mononuclear, whereas in bacterial infection the exudative stage is longer and the cells are predominantly polymorphonuclear (Iivanainen and Taskinen 1986). A rise in the CSF protein concentration and a fall in the CSF glucose concentration are also common. The cause of encephalitis has mostly been determined using screening batteries of many antibodies in repeated CSF and serum samples. A rise in antibody titres for a certain infectious agent during follow-up has been considered suggestive for the diagnosis. Confirmation may thus take several weeks, and for some infectious agents this is considered inadequate.
The problems in laboratory verification of HSVE have been debated for decades (Johnson et al. 1968) and biopsy has traditionally been suggested as the only reliable method (Hanley et al. 1987; Morawetz et al. 1983). Controversy exists over the risks and benefits of biopsy (Fishman 1987; Anderson et al. 1991), and recently the polymerase chain reaction (PCR) technique has been found valuable in the diagnosis of HSVE (Rowley et al. 1990; Aurelius et al. 1991; Lakeman and Whitley 1995). Consensus has now been reached by the members of the EU Concerted Action on Virus Meningitis and Encephalitis over the laboratory diagnostics to be used in HSVE. The use of PCR in combination with the detection of a specific intrathecal antibody response to HSV is considered confirmatory; biopsy is not required (Cinque et al. 1996). Eventually, the PCR technique will most likely become available for other viral infections, too.
2.3.3. Neurophysiological recordings
An electroencephalogram (EEG) often reveals abnormal brain activity in the acute stage. A generalised disturbance of background activity, bilateral slowing and occasional spikes are usually present in diffuse encephalitides. In focal diseases, periodic lateralised epileptiform discharges (PLEDs or periodical complexes) as well as focal slow waves may appear (Chatrian et al. 1964; PeBenito and Cracco 1979). This phenomenon is considered strongly suggestive of HSVE.
2.3.4. Neuroradiological imaging
Today, neuroradiology at the acute stage is crucial in excluding other causes, such as haemorrhage, tumours, infarction and trauma. In acute encephalitis, the tissue damage usually becomes visible only a few days after the onset of symptoms. Although both computed tomography (CT) and magnetic resonance imaging (MRI) may demonstrate oedema, focal hypodensities, haemorrhages and changes in ventricle size, MRI may be more sensitive in revealing the pathology (Schroth et al. 1987; Buttner and Dorndorf 1988; Weisberg et al. 1988). Lesions in the medial temporal lobes and basal forebrain are typical in HSVE (Hierons et al. 1978; Kapur et al. 1994; Yoneda et al. 1994)
Disturbances in brain perfusion as measured by brain perfusion tracers and SPECT have been observed in encephalitides. Both increased and decreased uptake of the lipophilic 99mtechnetium labelled perfusion tracer hexamethylpropyleneamineoxime (99mTc-HMPAO) occurs as a result of the inflammatory process (Launes et al. 1997b). Focal encephalitides, such as HSVE, have been found to cause a focal hyperperfusion, which later turns to hypoperfusion (Launes et al. 1988; Schmidbauer et al. 1991; McEwan et al. 1994). Simultaneously to HMPAO hyperfixation, hypofixation for 123I-iomazenil has been observed in HSVE (Launes et al. 1995). This newer tracer binds to benzodiazepine receptors and can measure neurone loss. Initial hyperperfusion in HMPAO-SPECT has been demonstrated to predict poor outcome in acute encephalitis (Launes et al. 1997b).
2.4.1. Cognitive functioning in Herpes simplex virus 1 encephalitis
One of the first descriptions of cognitive deficits after presumed HSVE was given in an article by Rose and Symonds (1960). They reported findings of four patients who survived the illness but were left with a permanent and severe impairment of recent memory with a long period of retrograde amnesia, although their intellectual functions were well preserved (Rose and Symonds 1960). Similar memory disturbances associated with temporal lobe lesions were shortly thereafter reported by Drachman and Adams (1962), who studied six patients with HSVE, three of whom survived.
Single cases of severe amnesia following HSVE have continued to dominate the neuropsychological literature of encephalitis. One of the most thoroughly studied patients is Boswell, by Damasio et al., different aspects of whose memory impairment have been described in several articles and handbooks (Damasio et al. 1985; Damasio et al. 1989; Damasio and Tranel 1990; Tranel and Damasio 1993). His amnesia is global, but nondeclarative priming and learning of perceptuo-motor skills and of affective valence occur (Damasio et al. 1989; Tranel and Damasio 1993). Intact implicit and short-term memory were also found in SS, another patient with severe amnesia after HSVE who has been studied at length (Cermak 1976; Cermak and O'Connor 1983; Cermak et al. 1988). There is evidence, however, that some processes of implicit memory (e.g. priming) may also be impaired in HSVE, whereas other processes (e.g. pursuit rotor learning) may remain intact (Kapur 1988).
Retrograde amnesia often accompanies anterograde amnesia. Intact anterograde memory in conjunction with retrograde amnesia is rarely encountered but dissociation between severe retrograde amnesia and only moderate anterograde amnesia has been reported in HSVE (O'Connor et al. 1992). Selectivity in retrograde amnesia has also been found in patients with HSVE, indicating subsystems in remote memory, such as a the ability to recall names, faces and episodes involving familiar or famous people (Warrington and McCarthy 1988; McCarthy and Warrington 1992; Eslinger et al. 1993).
Semantic deficit, anomia and agnosia
Aphasia is often encountered in encephalitis, HSVE in particular. The language defect is usually characterised by difficulty in naming, less commonly by a deficit in receptive speech. Some patients with HSVE have been found to be disproportionately impaired in naming certain categories - especially living things - compared with others (Barbarotto et al. 1996). When the category specificity has been studied in detail, it has occasionally been shown to appear in visual identification, drawing objects or sorting pictures in these categories (Warrington and Shallice 1984; Pietrini et al. 1988; Sartori et al. 1993; Mauri et al. 1994).
Difficulty in category-membership tasks and selective loss of visual imagery, specifically in living as compared with non-living items, were also found in one patient with prosopagnosia and object agnosia (Newcombe et al. 1989; Young et al. 1989; Mehta et al. 1992). Another patient presented impairment in the ability to recognise pictures of famous buildings accompanied by a loss of knowledge about them when tested from their spoken name (McCarthy et al. 1996). The patient also had prosopagnosia which did not explain the observed topographic amnesia.
The findings have been interpreted as proof of category specificity in the semantic systems in the brain (Warrington and Shallice 1984; McCarthy et al. 1996). The issue is under debate but similar findings have been made in other patients, too (for review, see Patterson and Hodges 1995; Semenza and Bisiacchi 1996). One explanation for these findings is that neural representation of different categories are located in separate cortical areas. An alternative, and perhaps more convincing, hypothesis is that an underlying featural organisation is anatomically distinct. Living things have many more perceptual features which are critical for their identification, whereas representations of man made artefacts are more heavily weighed towards functional terms (Garrard et al. 1997). Anatomically, the living - man-made dissociation seems to respect a division between the ventral temporal structures that are vulnerable in HSVE and fronto-parietal lesions, usually resulting from middle cerebral artery territory infarcts (Garrard et al. 1997). In a recent PET study naming animals selectively activated the left medial occipital lobe, whereas naming tools activated the left premotor area and an area in the left middle temporal gyrus (Martin et al. 1996).
It has been proposed that, depending on the extent of the lesion, different functional "levels" may be involved. Thus, a comparatively mild lesion restricted to one hemisphere would only produce a disturbed recollection of the names of certain items (amnestic anomia), but a more severe lesion spreading to the opposite hemisphere would result in further deficits in recognition and description of the same items (semantic memory impairment) (Pietrini et al. 1988). Nevertheless, the concept of semantic memory disorder somewhat obscures the distinction between aphasia, agnosia and amnesia traditionally made in clinical neuropsychology (Patterson and Hodges 1995).
Behavioural features associated with frontal dysfunction in HSVE have not been systematically studied very often, but adynamic aphasia, impulsivity and unresponsiveness, along with amnesia, have been noted in at least one patient (Brazzelli et al. 1994). Patients with HSVE have been found to perform normally in the Wisconsin Card Sorting Test but poorly in the Cognitive estimation Test and in the Word Fluency test (Leng and Parkin 1988; Shoqeirat et al. 1990). All these tests are used for measuring executive functions, although different lesion localisation within the frontal lobe has been suggested to correlate with impairment in these tests (Leng and Parkin 1988).
The effect of anti-viral treatment on cognition
Although the most effective therapy in HSVE today is acyclovir medication, its benefits in preventing cognitive deficits have not been systematically studied. A favourable neuropsychological outcome after acyclovir therapy has been described in two cases (Counsell et al. 1994) whereas Gordon and co-workers studied four acyclovir-treated patients with HSVE, and found all of them impaired in memory testing (Gordon et al. 1990). In the latter study the medication was initiated at a minimum of 5 days after the onset of symptoms.
2.4.2. Cognitive functioning in other encephalitides
In HZE, the specific neuropsychological sequelae after the acute stage have not been studied in detail although mental changes have frequently been observed. There are only a few case reports (Hall 1963; Horten et al. 1981; McKenna and Warneke 1992) dealing with psychological test results. One of the earliest concerns a patient with HZE who had retrograde amnesia for 30 years, was prone to confabulation and had a Korsakoff-type syndrome (Hall 1963). Two immunosuppressed cancer patients with HZE showed deterioration in both verbal and visual reasoning, perseveration, reversals, speech difficulty, and poor recent and remote memory (Horten et al. 1981). Deficits in attention, concentration, planning, impulse control and insight have also been observed after HZE (McKenna and Warneke 1992).
Defective memory is the most frequent symptom following any encephalitis. Amnesia of variable length and depth has been reported in single patients with encephalitis following EBV (Pommer et al. 1983), adenovirus (Wells 1971; West et al. 1985), HSV2 (Young et al. 1976) and Influenza A (Sulkava et al. 1981) infection, but no systematic neuropsychological studies have been conducted.
2.4.3. Psychiatric symptoms
In HSVE, psychiatric and behavioural symptoms have been reported to precede, accompany and follow the acute illness. In some patients, the altered behaviour and psychotic episodes are first observed long before the onset of neurological symptoms (Schlitt et al. 1985; Wilson 1976). A distinct feature of some patients with HSVE is Klüver-Bucy syndrome (Greenwood et al. 1983; Hart et al. 1986; Conlon et al. 1988). This syndrome, first described by Klüver and Bucy, appears in monkeys after bilateral temporal lobectomy including amygdala. It is characterised by an inability to differentiate between visual and auditory stimuli ("psychic blindness"), increased oral exploratory behaviour, loss of normal anger and fear responses, and heightened sexual activity (Klüver and Bucy 1939). The syndrome differs somewhat in humans, but bizarre eating, drinking, chewing and biting, altered emotional behaviour, abnormal sexual drive and visual agnosia have all been observed. The altered behaviour and residual mental symptoms of some survivors of HSVE probably led to their being confined to psychiatric institutes in the past (Hierons et al. 1978). On the other hand, increased levels of HSV antibodies have been found in hospitalised patients with psychotic depression (Rimon and Halonen 1969; Halonen et al. 1974; Lycke et al. 1974).
Psychic disorders are common at the initial phase of all encephalitides (Kennard and Swash 1981; Koskiniemi et al. 1981; Büttner and Dorndorf 1988). Acute psychotic episodes and visual hallucinosis are particularly common in HZE (Appelbaum et al. 1962; Jemsek et al. 1983; Ullmann and Kuhn 1988; McKenna and Warneke 1992). Late symptoms of fatigability, nervousness and psychic irritability have been reported following Kumlinge encephalitis in Finland (Wahlberg et al. 1989) and other tick-borne encephalitides in mainland Europe (Ziebart-Schroth 1972; Ackermann and Rehse Kupper 1979). Various psychiatric sequelae have also been observed in encephalitides following measles (Miller et al. 1956), HSV2 (Oommen et al. 1982), Influenza (Lloyd Still 1958) and Mycoplasma pneumoniae (Sterner and Biberfeld 1969). A distinct emotional reaction - hyperexcitability, hallucinations, mania, fear - accompanies rabies (Wood and Anderson 1988; Roine et al. 1988).
3. Aims of the study
The basic aim of the study was to determine the neuropsychological sequelae of patients with acute encephalitides treated with modern methods and anti-viral therapy. Specifically, answers were sought to the following questions:
4. Subjects and methods
4.1. Encephalitic subjects
During a 10-year period, between 1 January 1985 and 31 December 1994, 92 adult patients under the age of 75 with acute encephalitis were consecutively referred for neuropsychological examination at the Department of Neurology, Helsinki University Central Hospital. As the only hospital with 24-hour neurological emergency services in the province of Uusimaa (population 1 million), nearly all adult cases of serious CNS infections in this area are treated at this hospital. Some patients died at the early stage, and so could not be assessed. In addition, some patients with presumed encephalitis made a very rapid recovery and were not referred for neuropsychological examination. Patients with alcohol abuse or with coexisting or previous neurological disease were also excluded. Thus, 77 cases with acute encephalitis and without concomitant conditions were analysed.
The cases from 1985 to 1989 were collected retrospectively. The prospective series, which was collected from 1 January 1990 to 31 December1994, inclusive, consisted of 45 consecutive adult patients. No statistical differences in relevant background variables were found between the two groups (Table 3).
The diagnosis of encephalitis was based on the history, clinical physical and mental findings and EEG findings suggesting involvement of the brain parenchyma, CSF findings compatible with infection of the CNS, and CT excluding other causes. All patient files were reviewed by a single neurologist (J.L.), who confirmed the diagnosis in a systematic manner.
Chronic forms of encephalitis, such as Human Immunodeficiency Virus (HIV) infection or neurosyphilis, were excluded. Patients with vasculitis, meningitis or abscesses were also excluded.
The aetiology was established in 44 of the 77 (57%) patients. Standard laboratory methods available at the Helsinki University Central Hospital during the 10 year period were used. The PCR technique for detecting HSV-DNA became available for clinical use in 1993.
4.1.2. Anti-viral treatment
All patients received antibiotic therapy. Seventy-three patients, including all HSVE patients, were given intravenous acyclovir (30 mg/kg per day) for 11.2 ± 4.1 days. Acyclovir was not administered to one patient with Influenza B, one with TBE virus, one with epidemic nephropathy and one with suspected tuberculous meningoencephalitis, who were treated accordingly. Additional medication was used, when necessary. In the HSVE group, acyclovir was started on the same day as the mental symptoms appeared in two cases, on the next day in five cases, on day 2 in three cases, on day 3 in one case, on day 4 in one case, and 5 or more days after onset in five cases. All HZE patients had also been given intravenous acyclovir. Medication was started within 48 hours of the onset of mental symptoms in all but one patient (at day 28). The length of hospital stay was 36.4 ± 38.2 (range 8-213) days.
4.1.3. EEG recording
EEG was recorded with commercial equipment of Siemens Elema, and in individual patients with Cadwell Spectrum® equipment. The international 10-20 electrode placement system was used in all recordings. The first recordings were obtained within the first 3 days in 77% of cases. Follow-up recordings (1 - 7) were done in all but two cases.
4.1.4. Brain imaging
Neuroradiological imaging was performed on all patients with CT or MRI. CT was done with a Siemens Somatom DR®, Siemens HiQ® or General Electric 8800® scanner with additional contrast enhancement. The first CT was performed within the first 3 days of admission in 90% of cases. MRI was done with a 1.0T Siemens Magnetom unit or a 0.1T Mega4® (Instrumentarium Corp.). Axial T2-weighted spin-echo and T1-weighted images were obtained. Neuroradiological follow-up was performed using CT in 18 and MRI in 31 cases. The number, location and type of abnormalities were analysed. The size of the focal lesions was scored as small, medium or large. Cortical and central atrophy was scored as present or absent.
SPECT using 99m Tc- HMPAO was performed on 57 patients. Scanning was performed with a General Electric 400T rotating, large field of view gamma camera or a Picker DDC 4096 square detector gamma camera. For 77% of the patients the first scans were obtained within 10 days of admission; in 27 cases scanning was repeated one to three times during follow-up. For the study of perfusion defects in HZE, regions of interest were drawn on the anterior and posterior aspects of the images, and the anteroposterior perfusion (A/P) ratio was calculated as described in Roine et al. (1991).
4.2. Control subjects
Healthy control subjects (total 29) were enrolled as a reference group for the neuropsychological investigation. Twenty-five of the controls had initially volunteered for a study of quantitative EEG (Q-EEG) at the Institute of Occupational Health, and expressed their willingness to participate further. One control with a history of probable meningitis was excluded. The others had no medical problems, and their Q-EEG was normal. Five of the controls were additional volunteers who had no medical complaints and whose neurological examination was normal. Because the control group was used to produce cut-off points for impairment in individual tests, subgroups with comparable demographic features were formed for each study.
4.3. Study groups
This case study describes a patient who expressed an isolated retrograde amnesia without concomitant anterograde amnesia or other neuropsychological deficits. The patient, a 33-year-old right-handed woman with no relevant medical, psychiatric or family history, was one of a total series of 77 patients. Herpes simplex virus was clinically suspected, although not virologically confirmed, and intravenous acyclovir was administered on the fourth day after the onset of symptoms.
The characteristics of amnesia and the frequency of global amnesia were investigated in a prospective series of 45 patients with encephalitis. Twelve patients with anterograde amnesia in a neuropsychological assessment were compared with 24 patients who had no memory defects, and with 24 normal controls. The mean age of patients in the amnesic group was 34.3 ± 15.8 years, and they had 12.0 ± 2.9 years of education. The age of the patients without amnesia was 39.3 ± 14.6 and their length of education was 11.5 ± 4.1 years; for the control group the respective figures were 39.4 ± 9.5 and 13.5 ± 2.8 years. Thus, the three groups were comparable in these background vatiables.
The group of patients with amnesia was divided into two according to the aetiology. Four of the patients were diagnosed as having HSVE, one had adenovirus encephalitis, one had simultaneous elevation of CSF adenovirus and Borrelia antibody titres and one had encephalitis associated with rotavirus infection; in four the aetiology remained unidentified. The mean age of patients in the HSVE group (n=4) was 39.0 ± 17.6 years, and the length of education was 14.0 ± 3.6 years. In the non-HSVE group (n=7) the mean age was 27.0 ± 7.8 years and the length of education 11.4 ± 1.9 years. The groups were comparable in both respects.
Nine patients with Herpes zoster encephalitis in a total series of 77 patients were evaluated separately; none were immunosuppressed at the time of infection. Their age ranged between 25 and 73 (mean 55.7 ± 20.7) years, and the average length of their education was 9.4 ± 4.3 years.
The performance of the patients was compared with that of a group of normal controls (n=16). The mean age of controls was 52.0 ± 14.2 (range 26-73) years and they had, on average, 11.5 ± 2.9 years of education. The demographic variables of the controls were similar to those of the patients. There was no significant difference in the level of depression between patients and controls.
This follow-up study comprised the 40 of a prospective series of 45 (89%) who returned a mailed questionnaire on everyday functioning 3.7 ± 1.4 years after the onset of symptoms. Three (including two HSVE patients) of the five who did not reply had initially been intact in neuropsychological examination and had returned to gainful employment; two others had returned to work within a year of onset. Twelve patients with reported disability were re-examined neuropsychologically. The results of these two assessments were compared. Some data from an interim assessment are also presented.
The normative data for the neuropsychological tests were obtained from a group of healthy controls (n=25), who were 42.9 ± 13.5 years of age, and had, on average 12.2 ± 2.7 years of education. The age and education of the controls were not statistically different from those of the patients.
Adequate information about the length of transient amnesia in the acute stage was obtained for 65 of the 77 patients in the total series. Five of these 65 cases were excluded because disorientation and global amnesia persisted, and the amnesia could not be classified as transient. The study group therefore comprised 60 patients, who were divided into three groups according to the length of TENA: one day or less, 1-7 days, and more than 7 days from the onset. Age and length of education were similar in the three groups.
4.4. Neuropsychological assessment
The first neuropsychological examination was carried out as soon as the initial delirium had completely subsided and the patient could co-operate adequately. This was, on average, 27.5 ± 22.8, range 5-128, days after the onset of symptoms. The controls underwent a similar neuropsychological examination.
All patients with either anterograde or retrograde memory impairment, with or without other cognitive deficits in the first evaluation, were invited to a follow-up neuropsychological assessment 3 to 12 months after the onset. The second assessment included parts of the WAIS and the WMS II, and also other tests relevant for clinical purposes, which are not reported here.
The final neuropsychological evaluation was carried out, on average, 3.7 ± 1.4 years after the onset in patients with reported disability.
The test battery was constructed on the basis of previous knowledge of neuropsychological findings in acute encephalitis, and therefore from 1990 onwards special emphasis was placed on testing memory functions. To discriminate between specific memory deficits and more global cognitive decline, the test battery was designed to cover a wide range of other cognitive functions as well. Not all subtests are reported in all studies, only the relevant ones for each hypothesis being selected. All tests are listed below. Many of them are multifactorial, but they are grouped according to the functions they are believed to measure in clinical practise (Lezak 1995).
Verbal intellectual abilities
Verbal logical thinking was assessed using the scaled scores of the Wechsler Adult Intelligence Scale (WAIS) Information, Arithmetic and Vocabulary subtests (Wechsler 1955). The Verbal Intelligence Quotient (VIQ) was estimated from these three subtests. When the emphasis was on problem-solving ability (study III), only Arithmetic and Vocabulary were considered.
Non-verbal intellectual abilities
Non-verbal thinking and visual performance was assessed with the scaled scores of the WAIS Digit Symbol, Picture Completion and Block Design subtests (Wechsler 1955). The Performance Intelligence Quotient (PIQ) was estimated from these three subtests. When the emphasis was on problem-solving ability (study III), only Picture Completion and Block Design were considered.
The short-term memory tests (considered separately in study II only) were the Wechsler Memory Scale (WMS) (Wechsler 1954) Digit Span Forwards and Backwards, and a Luria-based task of Homogeneous Interference in which a subject is presented with two sequential word sets and then asked to recall both of them (Christensen 1975). Sets of two, three or four words were used, and the maximum score was 36.
Verbal episodic memory
Verbal memory was assessed with the WMS subtests Logical Memory and Associative Learning. In study III the raw scores were added together to produce one measure, elsewhere the raw scores were analysed separately. A tendency to benefit from verbal cues, an increased forgetting rate and confabulation were dichotomously scored in WMS Stories (reported in study II only).
Visual episodic memory
Visual memory was assessed with the WMS Visual Reproduction and the Benton Visual Retention Test (Benton 1974). In study III the raw scores were added together; elsewhere they were analysed separately. The Visual Recognition Memory task of Karolinska Sjukhuset (Ottosson 1960; Cronholm and Ottosson 1963) was included (reported in study II only). In this task the subject is presented with 30 pictures and then immediately asked to recognise them among distractors,
Tests for semantic memory (considered separately in study II only) comprised the scaled score of the WAIS Information subtest, confrontation naming of 30 pictures of living and non-living familiar objects (Ottosson 1960; Cronholm and Ottosson 1963) and five body parts, and comprehension of 11 sentences that included complex semantic-syntactic structures (Luria 1970). Note that some of these tests are also included under the heading language abilities, below.
The presence or absence of retrograde amnesia (RA) was estimated in a semistructured interview assessing retrieval of autobiographical episodes from days, weeks and months predating the onset of illness. In study I the Autobiographical Memory Interview (Kopelman et al. 1989) was additionally used to estimate the severity of the amnesia. The form consists of a Personal Semantic Memory questionnaire and an Autobiographical Incidents questionnaire, both tapping on memory of childhood, early adult life and recent events.
Transient encephalitic amnesia (TENA)
TENA was defined as the period of which the patient had no continuous day-to-day memories; it included periods of unconsciousness. It was assessed by a semistructured interview in which patients were asked to recall chronologically events prior to hospitalisation, during transport to the hospital and at the hospital. When memory gaps occurred, the patients were asked to reproduce the last episodes they could remember before the onset of symptoms, as well as the first episodes in the hospital of which they had a clear recollection. The amnesia period was then defined as the period between these two. Care was taken to differentiate between events the patients were actually able to remember and events they had been told about later.
Verbal functions were assessed with confrontation naming of body parts and pictures of familiar objects (maximum score 35), and comprehension of sentences (Luria 1970; Christensen 1975) with complex semantic-syntactic structures (maximum score 11). Study II includes Stroop colour naming task (Golden 1978) (correct responses out of a maximum of 84) and basic calculations (2 additions, 2 subtractions, 2 multiplication, 2 divisions) with a maximum score of 8.
Visuoconstructional functions were measured by asking patients to copy a cube and a Greek cross, and separately scoring each line produced correctly (maximum score 36), (Christensen 1975). A clock hand task (Christensen 1975) was used as a measure of visuo-spatial functions. Eight clocks, with one point for each correctly drawn clock hand and an additional point for errorless performance, produced a maximum score of 24.
Voluntary motor functions
Voluntary motor functions were measured by scoring patients efforts to imitate spatial movements and sequential movements with their arms, hands and fingers (Christensen 1975). An ordinal scale from 0 to 3 (no, mild, moderate and severe difficulty) was used.
Processing speed and flexibility
The speed of cognitive processes was assessed with the scaled score of the WAIS Digit Symbol subtest. The Stroop Test (Golden 1978), in which both colour naming time and colour-word interference time were measured, taps both speed and executive control. Verbal Fluency (oral output of words beginning with the letter K in one minute) (Benton 1968) was used as a measure of cognitive flexibility. The WMS includes a subtest of Mental Control (Wechsler 1954), which is discussed in study IV.
Personality and mood
The level of depression was assessed with the Beck Depression Inventory (Beck et al. 1961), in which scores of above 17 were considered to suggest significant depression (Kendall et al. 1987). Persistent psychiatric symptoms and personality change were assessed by interviews during follow-up visits.
Disability in everyday life
The patients functional capacity at discharge was assessed using a global four-point activities of daily living (ADL) scale: is independent in ADL, needs some assistance in ADL, needs daily assistance in ADL or is institutionalised. The Blessed Dementia Scale (Blessed et al. 1968) was used for more detailed screening of patients whose disability persisted during follow-up (study IV). In this scale a family member is asked to rate changes in the patients performance in everyday activities, in habits and in personality. Four points or more of the maximum of 28 are considered to indicate disability (Erkinjuntti et al. 1988). In a mailed questionnaire patients were also asked about their current emotional, cognitive and somatic complaints and their employment status.
Definition of deterioration in the neuropsychological measures
For the summative quotients VIQ, PIQ and MQ, a score of 95, the lower limit of the normal range in Finnish norms (Wechsler 1970; Wechsler 1975), was selected as the cut-off point for deterioration. None of the controls had a quotient lower than this.
In individual subtests, abnormal performance was defined as a raw score of more than 2 SDs below the mean of the controls. In tests in which controls had little variation (SD < 1.0), the lowest score was selected as the arbitrary cut-off point.
Amnesia in study II was operationalised as follows: memory defect was considered to exist if (1) the WMS MQ was below 95, (2) the subject produced less than 73% of the items in delayed retrieval of the WMS Stories (the lowest percentage of the controls), or (3) the subject had a discrepancy of more than 20 points between the WAIS Full Scale IQ and the WMS MQ.
One 70-year old patient was assessed using a Luria-based dementia battery (D-test) in all consecutive assessments in order to avoid a floor effect due to marked cognitive decline. The D-test, which provides age-corrected norms for impairment, comprises subtests of orientation, memory and intellectual functions, and tasks involving naming, semantic comprehension, visuo-practic and motor functions (Erkinjuntti et al. 1986; Ylikoski et al. 1990).
4.5. Statistical analyses
The difference in demographic variables (age and education) was assessed by analysis of variance (ANOVA) in comparisons of three groups, and Students t test in comparisons of two groups.
Continuous neuropsychological variables with distribution assumed close to normal (psychometric test results) were analysed using multiple analyses of variance (MANOVA) and subsequent ANOVAs, or Hotelling T2 with t tests, depending on the number of groups involved. The Tukey honest significance difference (Spjotfoll/Stoline test) was used for post-hoc pair-wise comparisons following ANOVAs. This test takes into account the difference in group sizes. Student t tests were performed using separate variance estimates whenever necessary. The homogeneity of variances was tested using Levenes test.
When the group sizes were small (< 10) or when the neuropsychological test variables were notably skewed, nonparametric statistics (Mann-Whitney U) were used for two-group comparisons. For variables measured on a nominal scale (dichotomous variables), the difference was evaluated using the Pearson c 2 test or the Fisher exact test for small group sizes.
The risk ratios (RRs) and the Mantel-Haenszel statistics for unfavourable outcome in the long TENA group compared with the short TENA group were calculated in study V, and Miettinens test-based upper and lower 95% confidence limits (CLs) were estimated (Jenicek and Cléroux 1982). RR was the ratio of the risk of exposure (ratio of long TENA patients with poor outcome to all patients with long TENA) to the risk of non-exposure (ratio of patients with short TENA with poor outcome to all patients with short TENA).
In the follow-up study (study IV), ANOVA for repeated measures and Wilcoxon matched pairs test were used to test the within-subjects difference.
All figures in the text are given as mean ± standard deviation (SD). In study II, the raw test scores were transformed into z-scores for better graphic comparability. They were standardised using the mean and SD of the controls. Elsewhere raw scores were used.
5.1. Isolated retrograde amnesia (study I)
The paper describes a 33-year-old patient with an interesting memory deficit. In the first neuropsychological evaluation, 17 days after admission, her intellectual abilities were above average, as were her overall memory quotient and performance in both verbal and visual memory tests. No confabulation was observed. Learning was intact, the forgetting rate was not accelerated, and orientation was normal. No circumscribed neuropsychological defects, such as aphasia, agnosia or apraxia, were found. No perseverative tendencies or signs of reduced mental flexibility appeared, and her word-fluency was normal. There was no clinical depression.
Despite her good performance in the routine neuropsychological assessment, retrograde amnesia was evident. Although she retained most of the personal facts (name, place and time of birth, address, school history etc.), amnesia was total for the previous 6 months and patchy for several years. Three months after the acute phase the patients autobiographical memory was assessed in greater detail (Figure 3). A structured interview revealed that her semantic memory of childhood and early adult life was intact, but that of recent times (before onset) was impaired. Her memory of autobiographical incidents from even further back in time was impaired. She also reported problems with the use of familiar items of household equipment such as a dish-washer. This may indicate a procedural (non-declarative) memory deficit.
Five months after the acute phase the patient still experienced problems in situations requiring memory of remote incidents. Otherwise she had been able to return to her normal daily life. In a mailed questionnaire 4 years later, the patient reported having returned to university.
The case represents a clear dissociation between anterograde and retrograde amnesia. Based on interviews with both the patient and her husband which revealed no existing or previous psychiatric problems, psychiatric aetiology was refuted. Although SPECT localised the lesion in the left temporal lobe, MRI remained normal, and specific anatomical correlates could not be found.
5.2. Frequency of global amnesia and analysis of anterograde memory disorder in encephalitides (study II)
Frequency of global amnesia
In the first assessment 24 of a prospective series of 45 patients had normal anterograde memory performance, and 21 had memory defects. Generalised cognitive deterioration was present in nine of the 21 patients, and amnesia (a specific memory impairment not associated with intellectual deterioration) in 12 of them (26% of the total of 45). In neuropsychological follow-up, the memory performance of nine patients had returned to the normal range, while three of the 12 with amnesia were found to have persistent anterograde amnesia.
Ten of the 45 patients, including the above patients with persistent anterograde amnesia, had retrograde amnesia of autobiographical material ranging from a few weeks to a few years. These three (6% of the total of 45 patients) were therefore found to have the typical features of global amnesia syndrome (Figure 4).
Quality of memory impairment
In the first assessment the 12 patients with anterograde amnesia performed, as a group, more poorly than controls in tests of short-term and episodic memory as well as of executive functions, but were similar to controls in the semantic memory tests. Digit span forward was in the normal range (from 5 to 8) in all 12 patients.
Because we wanted to find out whether the quality of amnesia in HSVE is different from that in other encephalitides, the group of patients with amnesia was divided into two groups according to aetiology. One patient was excluded because of severe depression. No statistically significant differences between the HSVE (n=4) and non-HSVE (n=7) groups were found in neuropsychological measures. The frequencies of mild confabulation, rapid forgetting and tendency to benefit from verbal cues were also similar in the HSVE and the non-HSVE groups.
The patients were then re-classified according to neuropsychological features (Table 4). Four of the 11 patients had semantic memory difficulties (anomia or difficulty in retrieving general knowledge in the WAIS Information subtest). Four patients had difficulty predominantly in executive functions (abnormal performance in the Stroop test or in the Word Fluency task), and they had a tendency to benefit from verbal cues. In the three remaining patients the increased forgetting rate was the most marked abnormal feature.
Our results indicate that HSVE does not lead to a homogeneous quality of amnesia. Moreover, other causes of encephalitis may lead to a similar pattern of amnesia.
5.3. Quality of memory impairment in Herpes zoster encephalitis (study III)
Cognitive deficits in HZE
In psychometric tests, the nine HZE patients as a group had a lower PIQ and more visual memory problems, and were slower in the Stroop tasks than the controls. A decline in problem solving and memory, and difficulty in word finding, calculation and visuoconstructional abilities were observed in some individual patients. The errors seemed partly to be attributable to inattentiveness and poor concentration. Other circumscribed neuropsychological deficits such as apraxia or agnosia were absent. Common features in several patients were slowness of thought and disinhibited behaviour (impulsivity, impaired planning, talkativeness) during the test performance. Mood changes, such as emotional lability, euphoria and depression were observed in seven patients. These behavioural features were still apparent at the follow-up examination of three patients at 3 months.
The neuropsychological findings in HZE are compatible with the concept of subcortical type cognitive impairment. Moreover, the few neuroradiological findings were mainly subcortical. SPECT revealed mostly frontal hypoperfusion, which can be interpreted as a reflection of subcortical dysfunction.
Comparison between HZE and HSVE
Because VZV belongs to the same group of viruses as HSV, it is of interest to compare the cognitive deficits associated with these two infectious agents. Figure 5 shows the frequency of different cognitive impairments in patients with HZE (n=9) and HSVE (n=17). Memory impairment was more frequent in HSVE, but behavioural disinhibition was more frequent in HZE (Fisher exact test p<0.05). Cortical deficits, such as apraxia, anomia and visuoconstructional dyspraxia, tended to be more common in HSVE although the differences did not reach statistical significance.
Six of the patients with HZE had retired before they fell ill. All three who had been working were able to return to their previous occupations. In the HSVE group six of the 13 patients originally employed (46%) returned to work.
5.4. Follow-up of the cognitive sequelae (study IV)
To evaluate the long term outcome in the prospective series of patients, we mailed a questionnaire, including the Blessed Dementia Scale (BDS), to all 45 patients an average of 3.7 years after onset. The BDS score of 28 patients was below 4, indicating normal performance in everyday activities, and that of 12 was 4 or above, indicating disability; five did not reply. There was a significantly larger number of patients with intractable epilepsy in the group with disability (4/12, 33%) than in the group with normal everyday performance (1/28, 3%). The 12 patients with difficulty in everyday life were invited to a follow-up neuropsychological investigation. One patient could not complete the test battery at follow-up because of frequent epileptic seizures.
At the follow-up assessment, five of the 11 testable patients had marked memory impairment together with other cognitive deficits (Figure 6). Eight patients had suffered from emotional instability or personality change during follow-up. This included panic and anxiety disorders, bipolar affective disorder with predominantly manic behaviour, aggressive outbursts and irritability, and depression. Klüver-Bucy syndrome was not encountered.
When initial assessments were compared with the follow-up assessments, an increase in the group means was observed in 15 of the 18 neuropsychological subtests. The number of subtests in which a patients performance was within the normal range (Test Performance Index, TPI, maximum value 18) was calculated separately for the first and last assessments, revealing an increase in the TPI in eight of 11 testable patients; in one patient there was no change and in two performance deteriorated. Figure 7 shows the change in MQ of each patient in all three available assessments: the first one at the acute stage, the second within the first year, and the third and final assessment at follow-up (ANOVA for repeated measures Rao R=5.72, p<0.05).
One third of the patients with acute encephalitis reported some kind of disability at follow-up. On close inspection, cognitive deficits were the primary cause of disability in only a few of the patients. Progressive deterioration was uncommon.
5.5. Transient encephalitic amnesia (study V)
The mean length of TENA in the 60 patients was 9.7 ± 22.2 days. Only 18 patients (30%) did not have amnesia, which suggests that TENA is quite common.
To determine the clinical significance of TENA we grouped the patients according to the length of TENA: £ 1 day (short TENA, n=26), of 1-7 days (n=17, medium TENA), and > 7 days (long TENA, n=17). Figure 8 shows the level of cognitive functioning in the three groups. In a pair-wise comparison, the long TENA group was more impaired than the short TENA group in WAIS PIQ, WMS MQ, delayed retrieval of WMS stories, WMS Figures and language abilities.
There were no differences between the three groups in the occurrence of brain atrophy, but the long TENA group had more severe focal brain lesions (hypodensities, infarction, haemorrhage, or focal oedema) in the first CT than did the short TENA group. The long TENA group also had greater difficulty in ADL than did the short TENA group. However, the percentage of patients able to return to their previous occupations was similar in all three groups.
Because epileptic seizures before or during hospitalisation were more numerous in the long TENA group, the above comparisons were repeated for patients without epileptic seizures. The results remained the same, however. The aetiology of the encephalitis (HSVE vs. other), and the latency between onset of symptoms and initiation of acyclovir treatment were similar in the three groups. Therefore, none of these possibly confounding factors accounted for the result. The length of the period of acute amnesia may have independent predictive value.
6.1. Issues in diagnostics and in neuropsychological measurement
The diagnosis of encephalitis is primarily based on the clinical picture. Although MRI is more sensitive in revealing the pathology, and may show typical lesions in the temporal lobes, brain imaging at the acute stage is helpful only in excluding other causes. In our study, the files on all patients were reviewed by the same neurologist, and thus the diagnosis is both systematic and uniform. Brain perfusion studies are useful in differentiating between focal and non-focal encephalitides. We used standard CSF and serum laboratory tests to establish the association between an infectious agent and encephalitis. Although a considerable number of our patients did not have a definite aetiology, the percentage of those who did (57%) is comparable to that in previous studies (Table 2). The diagnostic techniques have changed during the data collection period as more sensitive methods constantly become available. Since the present study focuses on the neuropsychological consequences of encephalitides, the accuracy of aetiological diagnostics is not, however, a vital issue in this study.
The study consisted of patients who were referred for neuropsychological examination, but did not include all those treated for presumed acute encephalitis at the Department of neurology. Care was taken to exclude patients with a doubtful diagnosis, concomitant neurological diseases or other types of CNS infection, such as meningitis or vasculitis. Patients who died at the early phase, as well as those who were discharged soon due to a very mild course of the disease were unavailable for neuropsychological assessment. Therefore, any bias in the inclusion of cases is bi-directional and probably does not distort the results.
A clinical neuropsychological examination is typically carried out using standardised tests of known reliability and validity (Miller 1992; Lezak 1995) Although dozens of memory tests have been constructed, only a limited selection is available in Finnish owing to the lack of normative data. This is especially so for tests of retrograde amnesia, in which cultural differences make simple translation of most tests impossible. Adequate tests for evaluation of semantic memory deficit are also lacking, since simple tests of naming are confounded by deficits in speech production.
The analyses of the theoretical models of memory using tests employed in clinical neuropsychology is problematic. Standard memory tests can be used for measuring change, for examining of impairment and diagnosis, for making case descriptions and assessments for rehabilitation and for conducting research, and no single test is ideal for all purposes (Mayes and Warburg 1992). Most of the tests designed to dissect the subsystems of memory processes in experimental set-ups and cognitive research have not yet been standardised for clinical use (Miller 1992; Mayes and Warburg 1992). On the other hand, the distinction between certain memory types (e.g. short-term memory and working memory) is still somewhat unclear, even theoretically.
Furthermore, neuropsychological tests are used in the assessment of amnesia and dementia, and the clinical diagnosis becomes operationalised through the tests. There is, however, no consensus concerning the cut-off scores that are diagnostic for amnesia (O'Connor et al. 1995). Neither has a clear decision been reached upon the extent of cognitive decline required for the diagnosis of dementia.
6.2. Amnesia in
6.2.1. Isolated retrograde amnesia
In clinical practice, discrete amnesia may arouse suspicion of psychogenic aetiology. New learning is often considered to be spared in psychogenic, but affected in organic, amnesias (Schacter et al. 1982; Kopelman 1987; Erickson 1990). During the last decade, however, several reports of cases with disproportionally severe retrograde amnesia have appeared in the literature refuting this claim. The aetiology in these patients has ranged from brain injury (Goldberg et al. 1981; Kapur et al. 1992; Markowitsch et al. 1993), HSVE (O'Connor et al. 1992) and hypoxia (Beatty et al. 1987) to transient global amnesia of unknown origin (Roman-Campos et al. 1980). In all of them anterograde amnesia has been present, although it has been milder than would be expected on the basis of the severity of retrograde amnesia. Patients with retrograde amnesia but without other neuropsychological findings are rare, and until the end of 1991 no such cases with a known diagnosis had been reported.
Our patient with isolated retrograde amnesia was hospitalised in October 1991 because of acute encephalitis. Herpes simplex was suspected but not verified. Later a similar case was reported in Japan (Yoneda et al. 1992). In both cases SPECT localised the lesion in the left temporal lobe, but CT and MRI were non-informative. In two cases of isolated retrograde amnesia reported earlier (Andrews et al. 1982; Kapur et al. 1989), diagnoses were not obtained and no radiological findings exist.
The structural lesions causing isolated retrograde amnesia are still not known, although several suggestions have been made based on patients with more widespread damage and other cognitive deficits. Lateral temporal lobes and insula (Damasio et al. 1985), parahippocampal and entorhinal cortices (O'Connor et al. 1992), the ventral tegmental area of the upper mesencephalon (Goldberg et al. 1981) and anterior temporal lobes lesions (Kapur et al. 1992; Markowitsch et al. 1993) have all been put forward as the primary sites for impairment. Some studies also stress the role of frontal lobes in autobiographical recollection (Kopelman 1991; Della Sala et al. 1993). Recently, the right temporo-frontal cortex has been suggested as the cause of autobiographical memory defect (Calabrese et al. 1996). All these studies, however, have been based on one patient only, and the contradictory findings call for further research.
6.2.2. Permanent global amnesia
Only 12 (26%) of the consecutive series of 45 patients, had amnesia at the first assessment. In 24 (53%), memory performance was in the normal range, and in 9 (20%) memory impairment was associated with more diffuse intellectual decline. The memory of nine patients improved during follow-up, and a pure amnesia syndrome was found in three patients (6% of the total of 45). In the HSVE group, the ratio was 1:8. Given the abundance of reports on global amnesia following encephalitis, especially in HSVE, the frequency found here was surprisingly low. Neuropsychological studies on amnesia in encephalitis have not described the pool of patients from which individual cases have been drawn (Cermak 1976; Greenwood et al. 1983; Damasio et al. 1985; Laurent et al. 1991; Counsell et al. 1994; Kapur et al. 1994), and thus previous literature may suggest an overestimated frequency.
6.2.3. Quality of anterograde amnesia
As a group, the amnestic patients shared the general features of the amnestic disorder. Digit span was intact, and semantic memory did not differ from the controls. Episodic memory was impaired, and some executive deficits were also found. Certain aspects of short-term memory were also impaired, since the results of both the interference task and the digits backwards task were poorer for the amnestic group than for the controls. Similar equivocal findings have been reported for the Brown-Peterson distraction task among other patients with amnesia (Shimamura 1989), indicating that tasks of this types may measure some other memory processes; attentional deficits may partially explain the findings.
Features of memory impairment after medial temporal lobe lesions are said to be preserved insight, a lack of confabulation, limited retrograde amnesia and a tendency towards rapid forgetting (O'Connor et al. 1995). In all our patients, confabulation was mild at most and retrograde amnesia was of limited duration. The three patients with global amnesia syndrome had lesions in the hippocampal complex, and their forgetting rate was increased, a finding compatible with the concept of temporal lobe amnesia. The increased forgetting rate was not a common feature in patients whose memory impairment was less persistent, despite of a hippocampal lesion in two of them. The sequelae may have been milder in our patients because of the unilaterality of the temporal lesions. In earlier reports, bilateral lesions after HSVE were common (Hierons et al. 1978; Kapur et al. 1994).
The HSVE group did not differ from the non-HSVE group in terms of short-term memory, episodic memory, semantic memory or executive functions. The large variances in the two groups together with the small size of the groups may obscure the differences, but HSVE did not seem to produce a homogeneous pattern of memory impairment. Grouping the patients by the neuropsychological profile instead of microbial cause revealed subtypes among the memory-impaired patients: those with predominantly semantic memory difficulty, those with frontal type disorder and those with rapid forgetting as the main feature; microbial cause was not the differentiating factor in any of them. Amnesia after encephalitis may appear in different forms, and no support for a unitary post-encephalitic amnesia syndrome was found.
6.2.4. Transient encephalitic amnesia
It is important to be able to determine the prognosis as accurately as possible, for the sake of both the patients and their relatives, as well as for the professionals deciding on the need for rehabilitation. So far, the only well demonstrated clinical parameters available for estimating the outcome in encephalitis have been age, delay of antiviral medication, level of consciousness at the onset of medication and aetiology (HSVE vs. non-HSVE). We compared patients with TENA£ 1 day and patients with TENA>7 days in a pair-wise manner, and found that an amnesic period of more than 7 days was associated with deficits in tests of memory and intellectual functions, and with difficulty in activities of daily living. Moreover, the relationship between TENA and cognitive outcome was linear, as the group of patients with medium TENA fell in the middle of these two groups in terms of neuroradiological findings, neuropsychological test performance and ADL.
Similarly to post-traumatic amnesia in brain injury, the length of the transient amnesia period seems to predict the outcome in encephalitis. As with all clinical predictors, however, some caution is called for. The risk of misclassification that exists in predicting the outcome for trauma patients using PTA (Joseph 1990; King et al. 1997) seems to exist for encephalitic patients, too. Even so, measuring the length of amnesia may help us to select patients who need detailed neuropsychological evaluation and rehabilitation. Furthermore, the fact that similar transient amnesia occurs both in trauma and in encephalitis, despite the difference in the injury mechanism, poses interesting questions concerning the phenomenon.
6.3. Neuropsychological findings in Herpes zoster encephalitis
The term "subcortical dementia" is used to describe a syndrome comprising forgetfulness, a slowing of thought processes, emotional or personality changes and impaired ability to manipulate acquired knowledge, but not aphasia or other cortical deficits (Albert et al. 1974; Cummings and Benson 1984; Brown and Marsden 1988). Some controversy and conceptual problems exist, however, regarding the classification of dementias as cortical or subcortical (Mayeux et al. 1983; Whitehouse 1986). Some of the defining features are psychometrically difficult to measure, and rely on qualitative analyses. Many of our patients with HZE had similar neuropsychological findings and features, although dementia was not common.
Behavioural changes, such as seen in our patients, can result from frontal lobe dysfunction as well as subcortical damage. Since the frontal and subcortical structures are connected by numerous neuronal tracts, the dysfunction of these systems share several clinical features (Nauta 1971; Albert et al. 1974; Goffinet et al. 1989; Brown and Marsden 1988). Excessive perseveration, typical of frontal lobe damage (Luria 1980), was not observed in our patients.
In a recent study, three distinct morphological patterns of brain damage were found after HZE : large/medium vessel vasculopathy with bland or haemorrhagic infarctions, small vessel vasculopathy with mixed ischemic/demyelinative lesions, and ventriculitis/ periventriculitis (Kleinschmidt-DeMasters et al. 1996). The pathogenesis may depend on the immunological status of the patient, a more severe outcome being likely for immunosuppressed patients. Our patients possibly fall into the second category, i.e. small vessel vasculopathy and demyelination might be responsible for the subcortical features observed. The subcortical type of cognitive impairment may not be specific for HZE, however. Subcortical dysfunction may occur in para- and postinfectious encephalitides, resulting in perivascular inflammation and demyelination (Ho and Hirsch 1985; Whitley 1990).
6.4. Neuropsychological outcome of Herpes simplex virus 1 encephalitis
Cognitive deficits were more frequent in the HSVE than in the HZE group. However, the variability was high, and some HSVE patients were cognitively intact. Five of the eight patients with HSVE in the prospective series had no major memory deficit after the first year. Only one of eight patients with HSVE was identified as having global amnesia. In a recent study of 10 patients with HSVE, Kapur and co-workers found dense amnesia in six and noticeable anterograde memory impairment in the remaining four (Kapur et al. 1994). The patients, however, were selected from among those with persistent memory complaints, which explains the high rate of amnesia.
The good outcome in HSVE was confirmed at follow-up. Four of the eight HSVE patients in our prospective series were rated as performing normally in everyday situations at an average of 3.7 years post-onset. Only two were found to have major cognitive deficits in neuropsychological re-evaluation; two others had emotional problems. Five HSVE patients (71%) of the prospective series, and six (46%) of the total series were eventually able to return to gainful employment. Considering that 20 years ago, less than a third of patients were lucky enough to survive the illness, this result can be regarded as remarkable.
One HSVE patient was observed to deterioration over the years. This patient suffered from intractable epilepsy, which may have affected the cognitive performance. In a follow-up study of five HSVE patients, Laurent and co-workers reported verbal amnesia and amnestic aphasia at the initial stage, but found substantial improvement at follow-up in all but one of the patients (Laurent et al. 1991), a finding similar to ours. Progression in HSVE seems to be rare nowadays.
The good outcome in our patients with HSVE is attributed to the fact that most of the radiological findings were unilateral. This is in contrast to previous neuropathological (Hierons et al. 1978) and MRI (Kapur et al. 1994) findings suggesting that the damage in HSVE is nearly always bilateral. Progression of the lesion from unilateral to bilateral used to be common (Koskiniemi and Ketonen 1981), but with the introduction of acyclovir therapy such advanced cases have become more rare, at least among our patients. Unilateral findings resulting in only mild neuropsychological sequelae have been reported in some more recent studies (Laurent et al. 1990; Laurent et al. 1991; Eslinger et al. 1993).
6.5. Recovery of cognitive
6.5.1. Improvement in follow-up
Twelve of 40 responders had difficulty in daily activities, and they were re-examined. Comparison of the results of the first neuropsychological assessment with the results of the follow-up assessment, showed an improvement in the majority of patients. In only two patients was consistent deterioration observed over the years, and in only one, an initially severely affected patient, was there no change. A similarly variable pattern has been observed in studies elsewhere on recovery of function after brain injury: 30-50% patients have been found to improve, 20-60% to remain the same and 10-30% to deteriorate (Ruff et al. 1991; Wilson 1992). Compared with these results, the long term prognosis in encephalitides does not seem any poorer.
Six of the 12 patients exhibited changes in personality and mood that were severe enough to interfere with daily living. Cognitive sequelae did not account for the disability in these cases. Psychiatric symptoms can be explained, on the one hand, by an emotional reaction to a possibly fatal illness and, on the other, by damage to the limbic system caused by encephalitis. HSVE in particular is known to affect these structures (Damasio et al. 1985; Damasio and Van Hoesen 1985; Kapur et al. 1994).
Four of the 12 patients suffered from intractable epilepsy. It may be argued that the frequent seizures were the main contributory factor in the cognitive decline of these patients. A high seizure frequency has been shown to have a detrimental effect on cognitive functioning (Dikmen and Matthews 1977; Seidenberg et al. 1981; Dodrill 1986); memory performance in particular may deteriorate because of epilepsy-related neuron loss in the hippocampus (Mouritzen Dam 1980).
6.5.2. Frequency of dementia
Twelve of 40 responders had difficulty in daily activities. At re-examination, five of them were found to have a persistent memory defect as well as other cognitive deficits. Thus, the frequency of dementia was 12.5 % among responders, and 11% among the total sample of 45. In a study from Denmark, the frequency of dementia was 15% in a series of 44 patients with acute encephalitis collected in 1976-87 (Sivertsen and Christensen 1996).
The evaluation of dementia depends very much on how we define the condition, and on the cut-off points used in neuropsychological tests. In an unselected series of 52 patients with stroke, dementia was found in three (6%) (Kotila et al. 1986). In that study, cut-off points for VIQ, PIQ and MQ were set at 85, compared with 95 in our study. Much higher estimates (up to 56%) for dementia after stroke have also been suggested (Ladurner et al. 1982). Considering these figures, the prognosis after encephalitis for our patients cannot be regarded as particularly grave.
6.6. Implications for the future
The study of memory has dominated research on encephalitides for several reasons. Memory processes offer a huge variety of aspects upon which to focus, irrespective of whether the viewpoint is clinical neuropsychology, cognitive psychology, behavioural neurology or neurobiology. From the patients point of view amnesia, especially in its "pure" form, in which intellect remains intact, is a dramatic and extremely incapacitating disorder. Furthermore, HSVE is considered ideal for neuroanatomical investigation and correlation with neuropsychological findings because of the limited but complete destruction of the temporal lobes and limbic system (Damasio and Damasio 1989). Since it tends to be difficult to test the theories of cognitive psychology on amnesic patients owing to the significant heterogeneity of lesions, many of the experimental studies have been carried out on HSVE patients.
Proper antiviral medication may, however, prevent the lesions from progressing bilaterally. The resulting lesions seem to be smaller and more variable, and the outcome of HSVE is more favourable than previously reported. Although our study was not designed to measure the effect of medication, we believe that the good outcome of the HSVE patients in our series was due to the fact that acyclovir medication was initiated as soon as possible, within the first four days of onset. It has been argued that acyclovir treatment decreases mortality but increases the relative frequency of cognitive deficits in surviving patients (Greenwood et al. 1983). Our findings suggest otherwise.
Infectious processes tend to be covered only briefly in neuropsychological handbooks, attention usually focusing on HIV and AIDS. If acute encephalitis is mentioned at all, a description of a single patient with dense amnesia, "aimless wandering in the hospital corridors" and profound Klüver-Bucy type behavioural changes following HSVE is given as a typical example (Lezak 1995). All our findings demonstrate the heterogeneity of both mnestic disorders and the outcome following encephalitides. Since patients with encephalitis are not uncommon in neurological units, it is surprising how few systematic neuropsychological data are available. More research is needed to clarify the cognitive sequelae of different types of encephalitis.
Because the prognosis of HSVE has been believed to be poor, neuropsychological rehabilitation has been considered futile. Our study implies that this belief needs to be reconsidered. Patients with encephalitis should be offered a chance for rehabilitation using similar indications to those for e.g. stroke or brain trauma. Research is still needed to evaluate the benefits of rehabilitation. We must learn to identify the individuals who will most probably benefit from intervention. The possible psychiatric sequelae, as well as the risk of intractable epilepsy, should be taken into account in follow-up, especially now that new improved medication is also available for these purposes.
The main findings of this study were:
Until now, there have been few detailed and systematic studies of the cognitive effects of encephalitis. These findings are significant both in clinical work and in research. Patients benefit from better awareness of the sequelae and estimates of outcome. Moreover, the observation of heterogeneity in the pattern of memory impairment is relevant to future scientific work.
First I want to express my gratitude to my supervisors Professor Veijo Virsu and Professor Matti Iivanainen, who have patiently guided me through this project. I also wish to thank the official reviewers, Matti Laine, Ph.D. and Aarne Ylinen, M.D., for their ideas and constructive criticisms in the thesis preparation.
I am indebted to Assistant Professor Markku Kaste, Head of the Department, for the opportunity to carry out this study in the Department of Neurology, Helsinki University Central Hospital (HUCH). I am also grateful to Professor Jorma Palo, who provided financial support when it was most desperately needed.
My kind thanks to Marja Hietanen, Ph.D., head of the Neuropsychology Unit in the HUCH, for her constant encouragement, and to all my colleagues Leena Hämmäinen, Lic.Phil, Maarit Leskelä, M.A, Erja Poutiainen, Ph.D. and Raija Ylikoski, Lic.Phil., who never grew tired of hearing about my scientific endeavours. I especially want to thank my colleague and friend Erja Poutiainen, with whom I have had the pleasure of collaborating in numerous projects in life. Taina Nybo, Lic.Phil, another colleague and friend, also deserves a word of appreciation for her capability of brightening up the day.
All co-workers in this study deserve my warmest thanks. I especially want to name Leena Valanne, M.D. and Oili Salonen, M.D. who placed their neuroradiological expertise at my disposal. Esko Matikainen M.D. at the Institute of Occupational Health, Helsinki is heartily acknowledged for his help in gathering the control group.
I am also grateful to all the patients who participated in this study.
Several people at the Department of Neurology during the past years - Kati Juva, M.D., Sari Kiuru, M.D., Hannu Laaksovirta, M.D., Ilkka Pieninkeroinen, M.D., Tarja Pohjasvaara, M.D., Jan Sirén, M.D., Pekka Tani, M.D., Risto Vataja, M.D., Auli Verkkoniemi, M.D., and many others - have by their presence created a stimulating, entertaining and supportive social network, which has been important to me.
In fact, the whole staff of the Department of Neurology, at the in-patient wards, at the out-patient clinic, at the out-patient rehabilitation unit, at the department library and at the administration, Ms Leena Hänninen in particular, should be acknowledged.
I want to express my gratitude to Timo Erkinjuntti, M.D. and Professor Raimo Sulkava, who were the first to lead me to the path of scientific research. Also, Ritva Laaksonen, M.A. has had an important impact on my training in clinical neuropsychology.
Associate Professor Jyrki Launes, M.D., my closest collaborator and husband, deserves my sincere gratitude. Without his involvement ever since the very beginning, I perhaps would never have had the strength to carry out my research project. It has been a pleasure to share these endeavours with him.
My parents, Vuokko Häkli-Hokkanen, M.D. and Professor Eero Hokkanen, have given me their warmest love and care, and have never ceased to support me in my pursuit of academic achievement. My brother, Jyrki Hokkanen, Ph.D. has led the way.
I thank my aunt, Ms Gillian Häkli, for revising the language of this thesis.
Financial support from Alfred Kordelin Foundation, Jenny and Antti Wihuri Foundation, and the Finnish Neurology Foundation is gratefully acknowledged.
Kauniainen, November 1997
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