Acute Symptomatic Seizures - DiVA portal1071723/... · 2017-02-22 · haematologic abnormalities),...

ACTAUNIVERSITATIS

UPSALIENSISUPPSALA

2017

Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1298

Acute Symptomatic Seizures

Clinical and Experimental Studies

IMAD HALAWA

ISSN 1651-6206ISBN 978-91-554-9812-2urn:nbn:se:uu:diva-314770

Dissertation presented at Uppsala University to be publicly examined in Gunnesalen iPsykiatrins hus, Akademiska sjukhusets kärnområde, Psykiatrins hus, Ingång 10, 751 85,Uppsala, Friday, 24 March 2017 at 13:00 for the degree of Doctor of Philosophy (Faculty ofMedicine). The examination will be conducted in English. Faculty examiner: Professor GuidoRubboli (Danish epilepsy center, Filadelfia/University of Copenhagen, Dianalund, Denmark).

AbstractHalawa, I. 2017. Acute Symptomatic Seizures. Clinical and Experimental Studies. DigitalComprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1298.52 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9812-2.

Epilepsy is defined as a condition with recurrent unprovoked seizures. When seizures arebelieved to be provoked they fall into another category of situation-related seizures, i.e. acutesymptomatic seizures (ASS). The definition of ASS is a clinical seizure occurring in closetemporal relationship with an acute insult in the central nervous system (CNS), which maybe metabolic, toxic, structural, infectious or inflammatory. The prognosis after unprovokedseizures and ASS differs with regard to risk of seizure recurrence and mortality.

This thesis focuses on seizures occurring in relation to common dysmetabolic conditions andsubarachnoid haemorrhage (SAH). Specifically, the occurrence of ASS in patients with differentlevels of hyponatraemia and hypoglycaemia was studied. Furthermore an experimental study inrodents was conducted to explore the relationship between chemically induced status epilepticus(SE) and hyponatraemia. In addition, seizures in relation to acute SAH were recorded and relatedto appearance of development of delayed cerebral ischemia (DCI). Finally, measurement ofneurofilament light (NFL) and tau in the cerebrospinal fluid (CSF) was performed.

In a large number of patients with hyponatremia a gradual increase (2.5 % – 11 %) inrisk of seizures with declining sodium levels was noted. Seizures were the only neurologicmanifestation of hyponatraemia in patients with moderately decreased sodium levels (> 115mM).

In a study of patients with hypoglycaemia, a notably low risk for seizures was found. Absoluterisk for neurological symptoms at glucose < 2.0 mM (95% CI) was 0.25 (0.13-0.41). This is afinding of potentially great clinical relevance, since seizures in the presence of hypoglycaemiaare often presumed to be acutely symptomatic.

In the animal study of acute hyponatraemia on kainic acid (KA) induced status epilepticus(SE) the hyponatraemic animals displayed an increased frequency of epileptiform activityand had longer duration of seizures. These results support the clinical observations thathyponatraemia aggravates SE.

In the study of patients with SAH seizures were frequent (36% of all patients) but did notpredict the development of DCI. Measurement of the CSF biomarker tau at different time pointsrevealed increased tau concentration between days 4 and 10, and may be associated with DCI.

Keywords: Seizure.

Imad Halawa, Department of Neuroscience, Neurology, Akademiska sjukhuset, UppsalaUniversity, SE-75185 Uppsala, Sweden.

© Imad Halawa 2017

ISSN 1651-6206ISBN 978-91-554-9812-2urn:nbn:se:uu:diva-314770 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-314770)

To my mother and the soul of my father

List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I. Halawa I, Andersson T, Tomson T. Hyponatremia and risk of sei-

zures: a retrospective cross-sectional study. Epilepsia, 2011 Feb;52(2):410-3.

II. Halawa I, Zelano J, Kumlien E. Hypoglycemia and risk of seizures:

a retrospective cross- sectional study. Seizure, 2015 Feb;25:147-49.

III. Zelano J, Halawa I, Clausen F, Kumlien E. Hyponatremia augments kainic acid-induced status epilepticus in the mouse: a model for dysmetabolic status epilepticus. Epilepsy Res. 2013 Sep;106(1-2):29-34.

IV. Halawa I, Vlachogiannis P, Amandusson Å, Elf K, Ronne-

Engström E, Zetterberg H, Kumlien E. Epileptic seizures and CSF concentrations of neurofilament light and tau proteins in patients with subarachnoid haemorrhage. Manuscript.

Reprints were made with permission from the respective publishers.

Contents

Introduction ................................................................................................... 11Acute symptomatic seizure ....................................................................... 11Epidemiology ............................................................................................ 12Causes of acute symptomatic seizures ...................................................... 12Specific causes of acute symptomatic seizures ........................................ 12ASS in association with hyponatraemia and hypoglycaemia .................... 14Hyponatraemia and status epilepticus ...................................................... 15Hypoglycaemia and seizures .................................................................... 15Status epilepticus ...................................................................................... 16Animal models of status epilepticus (SE) ................................................. 16Subarachnoid haemorrhage ...................................................................... 17Delayed cerebral ischemia ........................................................................ 17Seizures in SAH ........................................................................................ 18Biomarkers in brain injury – neurofilament light and tau ........................ 19

Prognosis and treatment of ASS ................................................................... 20

Aim of the thesis ........................................................................................... 21

Materials and methods .................................................................................. 22Design and setting (paper I and II) ........................................................... 22Patient and data collection (paper I and II) ............................................... 22Animal and data collection (paper III) ..................................................... 23Patient and data collection (IV) ................................................................ 24Statistical methods .................................................................................... 25Ethics ........................................................................................................ 26

Results ........................................................................................................... 27Paper I ....................................................................................................... 27Paper II ..................................................................................................... 28Paper III .................................................................................................... 29Paper IV .................................................................................................... 33

Discussion ..................................................................................................... 36Hyponatraemia and risk of seizures .......................................................... 36Hypoglycaemia and risk of ASS .............................................................. 37Hyponatraemia and SE ............................................................................. 37

Acute symptomatic seizures in SAH ........................................................ 38Biomarkers in SAH .................................................................................. 38Limitations ................................................................................................ 39

Conclusions ................................................................................................... 41

Future directions ............................................................................................ 42

Summary in Swedish/ Populärvetenskaplig sammanfattning ...................... 43

Acknowledgement ......................................................................................... 45Financial support ...................................................................................... 46

References ..................................................................................................... 47

Abbreviations

ASS Acute Symptomatic Seizures aEEG Amplitude-integrated EEG CA Cardiac Arrest CI Confidence Intervals CNS Central Nervous System cEEG Continuous EEG CSF Cerebrospinal Fluid CT Computed Tomography EVD External Ventricular Drainage DM Diabetes Mellitus DDAVP 1-deamino-8-D-arginine vasopressin EEG Electroencephalography ES Electrographic seizure GCSE Generalised convulsive status epilepticus ICP Intracranial Pressure ILAE International League Against Epilepsy KA Kainic acid MRA Magnetic Resonance Angioagraphy MRI Magnetic Resonance Imaging NFL Neurofilament light NCS Nonconvulsive seizure NICU Neuro-intensive Care Unit SE Status Epilepticus TBI Traumatic Brain Injury TCD Transcranial Doppler SAH Subarachnoid haemorrhage NFL Neurofilament light

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Introduction

Epilepsy is a common disorder, occurring in all countries and all age groups. When a person has an epileptic seizure it is often believed that he or she suffers from epilepsy. However, epilepsy is defined as a condition with re-current, unprovoked seizures. In the most recently updated definition of epi-lepsy according to the ILAE, epilepsy is a disease of the brain defined by any of the following conditions: (1) at least two unprovoked (or reflex) sei-zures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.[1]

Epilepsy is classified according to underlying cause; genetic, structur-al/metabolic or unknown. Seizures are dichotomised into those that are gen-eralised and originating at some point within the brain, and rapidly engaging, bilaterally distributed networks. Focal seizures, on the other hand, are be-lieved to originate within networks limited to one hemisphere.

When seizures are assumed to be provoked, they fall into another catego-ry termed situation-related seizures,[2] and the medical investigation, treat-ment and prognosis of these seizures differs considerably from those of un-provoked seizures.

Acute symptomatic seizure Acute symptomatic seizure (ASS), which is also known as reactive seizure, provoked seizure or situation-related seizure, is defined by the International League against Epilepsy (ILAE) as a clinical seizure occurring in close tem-poral relationship with an acute central nervous system (CNS) insult, which may be metabolic, toxic, structural, infectious or inflammatory[2]. Quite surprisingly, despite its clinical relevance, ASS has received very little atten-tion in the scientific literature.

The prognosis after unprovoked seizures and ASS differs with regard to the risk of seizure recurrence and mortality; therefore, it is essential to define the underlying conditions in which acute symptomatic seizures occur.[3]

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Epidemiology There are few epidemiological studies on the incidence of acute symptomat-ic seizures. When reported the incidence is 29-39 per 100 000 a year[4, 5]. Acute symptomatic seizures represent about 40% of all afebrile seizures[6].

An age-specific incidence of ASS has been found in different studies,[4, 7] with the first year of life accounting for the highest incidence by far. The incidence then declines and reaches a nadir of 15 per 100 000 persons/year at 22–34 years of age. After 35, the incidence increases progressively and reaches 123 per 100 000 persons/year among persons older than 75 years of age[4, 5].

The risk of experiencing an acute symptomatic seizure during an 80-year life span is 3.6%, which approaches the risk for epilepsy[8]. The prevalence of a history of ASS is somewhat lower than the cumulative incidence be-cause of the high mortality rate associated with many of the causes of ASS

Causes of acute symptomatic seizures Acute symptomatic seizures can be associated with a primary brain insult or systemic disturbance. It has been suggested that ASS are events occurring within one week of stroke, traumatic brain injury, anoxic encephalopathy or intracranial surgery. Symptomatic seizures also can occur at first identifica-tion of subdural hematoma, in the presence of an active central nervous sys-tem (CNS) infection, or during an active phase of multiple sclerosis or other autoimmune diseases. In addition, ASS may appear in the presence of severe metabolic derangements (documented within 24 h by specific biochemical or haematologic abnormalities), drug or alcohol intoxication or withdrawal or exposure to a well-defined epileptogenic drug [2].

Specific causes of acute symptomatic seizures

Cerebrovascular lesions Between 5-10% of individuals with a stroke experience a seizure within one week of an acute stroke. The frequency varies with the nature of stroke, with a higher incidence observed in haemorrhagic stroke, younger patients and individuals presenting with higher pre-stroke Rankin scores. Subarachnoid and intracerebral haemorrhages are also risk factors for ASS [9, 10].

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Traumatic brain injury (TBI) Severe concussion can be accompanied by brief convulsive movements[11]. The occurrence of seizures has been reported in up to 6% of patients who experience a traumatic brain injury (TBI)[12-14].

Encephalopathy Cardiac arrest (CA), respiratory failure, carbon monoxide poisoning or other causes of hypoxic encephalopathy may provoke acute seizures within one week. A subgroup of patients who suffers from CA develops post anoxic status epilepticus, which is associated with poor outcome[15].

Cerebral infections and inflammatory-immune conditions Acute symptomatic seizures occurring within 7 days of an acute CNS infec-tion affect 2-67% of patients with encephalitis[16]. Evidence for ASS occur-ring in the context of autoimmune encephalitis is increasing[17-19]. Seizures in relation to encephalitis are probably underestimated because non-convulsive seizures and status epilepticus are difficult to diagnose in con-fused or comatose patients.

Drug withdrawal and toxic insults Abstinence seizures in patients who abuse alcohol, benzodiazepines or relat-ed sedative drugs are not uncommon, especially in adolescents and adults[20-22]. Indicators of ASS associated with alcohol withdrawal are a history of abuse and generalised tonic-clonic seizures with other symptoms of withdrawal, such as tremors, sweats and tachycardia. The seizure must have occurred within 7-48 h of the last drink. Some neuroactive medications and illicit drugs may also provoke seizures[23, 24].

Metabolic derangements Metabolic abnormalities are commonly encountered in clinical daily prac-tice. The neurological manifestations reflect the severity of the derangement and require correct diagnosis for emergency treatment of the underlying metabolic disturbance. Acute and severe electrolyte imbalances can exhibit with progressive neurological symptoms including seizures and have been reported in patients with hyponatraemia, hypocalcaemia and hypomag-nesaemia[25]. Severe low blood glucose is a medical emergency condition. It can cause a variety of symptoms including confusion, loss of conscious-ness and seizures[26]. Hyperglycaemia has also been recognised in associa-tion with seizures[27].

ASS has also been reported in connection with uraemia due to renal fail-ure and in other rare causes including thyrotoxic storm and porphyria[28].

Cut off values for metabolic disorders where seizures should be consid-ered acutely symptomatic rather than unprovoked are based, at best, on case

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studies[25]. There are few systemic studies that provide a definite value for each metabolic disorder. However, the Epidemiology Commission of the ILAE has suggested guidelines and proposed cut off values for acute sei-zures to be considered as ASS. These values are presented in the following table[2]:

Table 1. Cut off values for metabolic disorders and risk of seizures. Biochemical parameter Value S-glucose <2.0 mM S-sodium <120 mM S-magnesium <0.3 mM S-calcium <1.2 mM S-urea >35.7 mM S-creatinine > 884 mM

ASS in association with hyponatraemia and hypoglycaemia Hyponatraemia is a well-known aggravating factor for seizures[29-32] and is common in clinical practice. Defined by a plasma concentration below 135 mM, it is the most frequent metabolic electrolyte disturbance in emergency departments. The major clinical complications from acute hyponatraemia are brain swelling and herniation when sodium values approaches 120 mM. The fall of serum sodium is proportionately associated with reduction of serum osmolality.

Serum osmolality and renal water excretion is regulated by the anti-diuretic hormone (ADH) (also called Vasopressin). Patients who develop hyponatraemia have impaired ability to suppress the secretion of ADH. However, massive water ingestion or defect in the urinary concentrating mechanism cause hyponatraemia in spite of suppression of ADH.

The fall in plasma osmolality causes osmotic movement of water from the hypotonic extracellular space into relatively hypertonic cells that lead to cellular and cerebral oedema. The opposite movement of intracellular water to the extracellular space leads to cellular dehydration and in the brain this can cause central pontine myelinolysis. The speed with which hypo-natraemia develops affects the seizure risk.[33, 34] Acute hyponatraemia developing in less than 48 hours causes symptoms due to the lack of cerebral adaption. Conversely, chronic hyponatraemia that develops slowly and grad-ually is usually asymptomatic because of the adaptive capacity of the brain to compensate by losing osmolytes.

Hypornatraemia is associated with high morbidity (osteoporosis)[35, 36] and mortality in diseases like myocardial infarction, heart failure, liver cir-rhosis and kidney diseases[37], [38, 39].

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The condition can arise for several reasons, including administration of drugs such as desmopressin[40] and diuretics, tricyclic antidepressants and serotonin reuptake inhibitors and side effects from antiepileptic drug treat-ment [41]. Acute onset hyponatraemia is particularly common in patients who have undergone any type of brain insult, including traumatic brain inju-ry, subarachnoid haemorrhage and brain tumours, and is a frequent compli-cation of all kinds of intracranial procedures. Polydipsia, commonly seen in patients with psychiatric disorders, is another cause of hyponatraemia with risk of seizures.

Hyponatraemia and status epilepticus Hyponatraemia is significantly associated with status epilepticus (SE) refrac-tory to treatment, indicating the importance of studies on this particular dysmetabolic condition[42]. There is little experimental data on SE in hypo-natraemia. Seizures in hyponatraemia have been studied mostly in the con-text of seizure thresholds or very severe hyponatraemia causing brain oede-ma, herniation and death. Hypotonic hyponatraemia is known to reduce the threshold for electrically induced seizures[43, 44], as well as chemically induced seizures in relation to renal failure[45]. However, these studies have not clarified the effect of hyponatraemia on SE severity or duration. Little is known about appropriate treatment strategies for SE and co-existing hypo-natraemia.

Hypoglycaemia and seizures Clinical hypoglycaemia is, by definition, a plasma concentration low enough to cause symptoms or signs including impairment of brain function[46]. Neuroglycopaenic symptoms are a direct result of brain glucose deprivation. Systemic glucose balance is normally maintained by regulation of endoge-nous glucose production from the liver and kidneys and of glucose utilisation by tissue outside the CNS like muscle.

Under normal conditions, glucose is the exclusive fuel for the brain. Un-like other organs, the brain cannot synthesise glucose or utilise physiologic concentrations of non-glucose fuels effectively.

When the brain receives insufficient glucose to meet its metabolic needs (neuroglycopaenia), an autonomic response is triggered to mobilise storage deposits of glycogen and fat. Hepatic glycogen reserves and gluconeogenesis from the liver and kidney directly supply the central nervous system with glucose, while the mobilisation of fatty acids from triglyceride depots pro-vides energy for the large mass of skeletal and cardiac muscle, renal cortex, liver and other tissues that utilise fatty acids as their basic fuel, thus sparing glucose for use by the tissues of the central nervous system[47]. Symptoms

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include cognitive impairments, behavioural changes, psychomotor abnor-malities, seizures and coma.

Hypoglycaemia is common in patients with diabetes. Hypoglycaemia is a fact of life for many persons with diabetes mellitus type 1 (T1DM). The aver-age patient with T1DM suffers two episodes of symptomatic hypoglycaemia per week, thousands of such episodes over a lifetime, and one episode of temporarily disabling hypoglycaemia, often with seizure or coma, per year. An estimated 2–4% of people with T1DM die from hypoglycaemia [46, 48].

Status epilepticus Status epilepticus (SE) is a frequent neurological emergency with case fatali-ty rates ranging from 7.6 to 39% in population-based studies[49-51]. Several independent predictors of poor outcome have been recognised, including advanced age, de novo presentation, impairment of consciousness before treatment and seizure type, but the most critical factor by far is the underly-ing aetiology[52]. Although much attention has been paid to cessation of seizures by administration of different antiepileptic drugs (AED), it is far more critical to treat the underlying aetiology. Indeed, some aetiologies such as stroke, severe metabolic disturbances, alcohol withdrawal or intoxication, brain tumour–related events and infections need emergent and specific treatments beyond seizure medication[53].

A recently published definition states that SE is a condition with a pro-longed seizure that might lead to long-term consequences including neuronal death, neuronal injury and alteration of neuronal networks, depending on type and duration of SE. The time when the seizure is likely to be prolonged leading to continuous seizure activity is dependent on seizure type, but in most cases > 5 minutes. Long-term consequences are likely to appear if sei-zure duration exceeds 30 minutes.

Animal models of status epilepticus (SE) Comprehension of the complex mechanisms underlying seizure generation cannot be fully acquired in clinical studies with humans. As a result, the use of appropriate animal models is essential. Kainic acid (KA) was one of the first compounds used to model epilepsy in rodents[54]. It is an L-glutamate analogue, the systemic or intracerebral administration of which causes neu-ronal depolarisation and seizures. There are several models of SE. Among the simpler ones are KA-induced seizures, which have the advantage of not requiring a kindling setup. Kainic acid is comparably easy to control, robust in the induction of SE and has an increased survival rate, which reduces var-iability.[55]

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Subarachnoid haemorrhage Subarachnoid haemorrhage (SAH) is a severe condition with high morbidity and mortality with an incidence of 9 per 100 000[56]. The signs and symp-toms of SAH range from subtle prodromal events to severe and sudden headache[57]. The headache is often associated with nausea, vomiting, focal neurological deficits and meningism[58]. Altered level of consciousness is found in many patients. Diagnosis of SAH is best performed by a head com-puted tomography (CT) scan[59, 60]. Lumbar puncture (LP) is obligatory if the CT is negative and there is a strong suspicion of SAH[60, 61]. Typical findings in SAH are elevated opening intracranial pressure (ICP) and an increased red blood cell count. Spectrophotometry can detect products from the haemoglobin catabolism; oxyhaemoglobin, methaemoglobin and biliru-bin.

Delayed cerebral ischemia The most devastating complication of SAH is delayed cerebral ischemia (DCI). DCI is defined as new focal or global neurological deficits and/or new cerebral infarction on computed tomography (CT) that is not caused by rebleeding or acute hydrocephalus[62]. Signs of DCI occur in about 30% of patients, typically appear between days 4 and 10 following SAH and are the major causes of morbidity and death[63, 64]. The pathophysiology of DCI is not fully understood. The mechanism is a complex of many factors but cere-bral arterial vasospasm is thought to be a major contributing factor. Other mechanisms, such as early cell death and the initiation of inflammatory reac-tion[65], cortical spreading depolarisation[66] and dysfunction of cerebral autoregulation[67, 68] probably play a major role.

A major challenge in the management of SAH is early identification of DCI, thereby enabling therapeutic interventions. Clinical deterioration at-tributable to DCI is a diagnosis after exclusion of other causes (such as in-fection, hypotension, hyponatraemia and others), and it is especially difficult in patients who are comatose or sedated. Risk factors for developing DCI are poor clinical status with a high grade on Hess and Hunt grading scale and extent of bleeding (see Fischer scale).

Cerebral ischemia is best detected by clinical monitoring in combination with Magnetic resonance imaging (MRI) (including diffusion-weighted im-aging, angiography and perfusion), computed tomography (CT) (angi-ography and perfusion), transcranial Doppler (TCD) and sometimes digital subtraction angiography.[62, 69]

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Hunt and Hess grading scale

1 Asymptomatic, mild headache, slight nuchal rigidity

2 Moderate to severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve palsy

3 Drowsiness/confusion, mild focal neurologic deficit

4 Stupor, moderate-severe hemiparesis

5 Coma, decerebrate posturing

The Hunt & Hess grading scale was developed in 1968 as a clinical tool to predict the outcome of SAH. Higher grade is considered to associate with severe out-come[70, 71].

Fisher grading scale for SAH

The Fisher grading scale was developed in 1980 to predict cerebral vasospasm after SAH by using the CT scans during 5 days of SAH. It means that localised clotting or diffuse blood larger than 1 mm is predictive of cerebral vasospasm[72].

Seizures in SAH Acute symptomatic seizures (ASS) have been reported to occur in 6-24% of patients with SAH[73, 74]. Continuous electroencelography (cEEG) allows monitoring of patients with acute aneurysmal subarachnoid haemorrhage for detection of non-convulsive seizures and non-convulsive status epilepticus. Both clinical and electrographic seizures (ES) are believed to have a nega-tive impact on the outcome[75]. Continuous EEG has also been used for surveillance and early recognition of DCI[76].

1 No haemorrhage evident

2 Subarachnoid haemorrhage less than 1 mm thick

3 Subarachnoid haemorrhage more than 1 mm thick

4 Subarachnoid haemorrhage of any thickness with intra-ventricular haemorrhage or parenchymal extension

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Non-convulsive seizures Nonconvulsive seizures (NCS) also known as subclinical seizure or electro-graphic seizure (ES) are identified by continuous EEG monitoring. NCS are common in comatose patients has been described in 8% to 30% of comatose patients [75, 77, 78]. NCS is treatable and reversible condition and is consid-ered to have a negative impact on the outcome in some neurological condi-tions such as SAH [75].

While EEG is a non-invasive, and largely available test, it is limited by the absence of a universally accepted classification system and by its suscep-tibility to sedation and metabolic conditions [79, 80].

Criteria for definition of non-convulsive seizures in this thesis are abnor-mal paroxysmal events that are lasting at least 10 seconds and are different from the background, including spikes, sharp waves, or sharp-slow wave complexes either at a frequency of at least 3 per second or, if lower, of at least 1 per second and with clear evolution in frequency, morphology, or location[81] [82].

Biomarkers in brain injury – neurofilament light and tau A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or re-sponses to a therapeutic intervention. Significant efforts have been made to study different biomarkers as potential tools for predicting vasospasm and outcome after SAH[83]. Biomarkers of neuronal and axonal damage can be used to diagnose brain injury and predict clinical outcome. Cerebrospinal fluid (CSF) markers are preferred, owing to their proximity to the brain. Cerebrospinal fluid is in direct contact with the extracellular matrix of the brain and reflects biochemical changes that occur in the brain. Cerebrospinal fluid biomarkers that reflect neuronal damage have recently been studied.

Neurofilament light chain protein is a cytoskeletal constituent of interme-diate filaments, and is thought to reflect neuronal and axonal injury when appearing in the CSF. Tau is located in the nerve axons in the brain, prefera-bly in thin non-myelinated cortical axons. Its function is to bind to microtu-bules in axons and thereby stabilise these[84].

High concentrations of NFL and tau have been reported in the first days after the initial injury in SAH and extending into the period of DCI, and correlate with poor long-term outcome[85] [86].

NFL is a marker that reflects subcortical damage, while tau is more relat-ed to cortical brain injury[84].

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Prognosis and treatment of ASS

Seizures occurring as a consequence of metabolic imbalance or structural brain damage do not entail a diagnosis of epilepsy. Early identification of the aetiology of provoked seizures is necessary for correct management. Treat-ment of ASS differs from unprovoked seizures. Antiepileptic treatment may be needed in the acute phase, but is not usually needed in the long term. Acute symptomatic seizures are unlikely to reoccur unless the underlying acute causal condition reoccurs. The risk of subsequent epilepsy is increased in a subgroup of patients, especially in cases with associated cerebrovascular disorders, head injuries and central nervous system infection[87].

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Aim of the thesis

This thesis focuses on studies of occurrence and risks of acute symptomatic seizures (ASS) in different clinical and experimental settings. The specific aims are:

! To study the risk of seizures at different levels of hyponatraemia.

! To study the risk of seizures at different levels of hypoglycaemia.

! To explore whether kainic-induced status epilepticus in the mouse

could be a suitable model for experiments on status epilepticus un-der acute hyponatraemia.

! To test the hypotheses that seizures are associated with poor out-

come in patients with subarachnoid haemorrhage.

! To explore the association between CSF concentrations of neurofil-ament light (NFL) and tau and delayed cerebral ischemia as out-come.

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Materials and methods

Design and setting (paper I and II) The design was retrospective, cross-sectional observational cohort study in both papers.

To identify patients with hyponatraemia, the database of the Biochemical Laboratory at Gävle County Hospital in Sweden, serving a catchment area of approximately 170 000 inhabitants, was systematically searched within a 3-year period (March 2003 to August 2006).

The study in paper II was performed at Uppsala University Hospital, which is an academic care centre serving a primary population of approxi-mately 300 000 people with 59 151 patient admissions per year. The data-base of the biochemical laboratory at the hospital was scrutinised for low blood glucose values for one year (January to December 2009).

Patient and data collection (paper I and II)

Identification of patients In paper I, a total of 363 individuals who had been admitted as inpatients to Gävle County Hospital and had their serum sodium level measured as part of routine hospital procedures were included. Serum sodium levels were cate-gorised as follows: <110 mM, 110–114 mM, 115–119 mM, and 120–124 mM. For the three lowest serum sodium categories, all identified cases were included. For the 120–124 mM category, 150 patients were randomly select-ed from a total of 1 105 patients who had a serum sodium level within that range. Beginning with the lowest serum sodium levels, a search was per-formed for each case with the corresponding medical record. All selected medical records were carefully checked for information on a seizures occur-ring within 24 h of the sampling time (as recommended by the ILAE Com-mission, 1993[2]), along with demographic and clinical variables.

In paper II, a search was performed in the laboratory database at Uppsala University Hospital for all patients with blood glucose values ≤ 3.5 mM. The inclusion criterion was patients who had been admitted to the hospital for medical evaluation. Exclusion criteria were insufficient medical records and a history of epilepsy or documented non-metabolic risk factors for ASS (e.g.

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stroke, CNS infection, traumatic brain injury, anoxic encephalopathy or oth-er lesions in the CNS). In total, 388 patients were included, and for each case the corresponding medical records were scrutinised.

Data collection (paper I and II) The variables recorded for the studies included age, gender, documented comorbidity, seizure type (ILAE Commission, 1981) and timing, and other abnormal biochemical and haematological values when available (e.g. glu-cose, urea, sodium, calcium, magnesium, ammonia and creatinine) and de-tected within 24 h of the seizure. All data were anonymised prior to analysis.

Animal and data collection (paper III)

Animals Female mice C57/BL6 mice that were at least seven weeks old (acquired from Taconic ®) were used. All mice were group housed, maintained on a 12-hour day/light circle and cared for according to current animal regula-tions.

EEG sampling Electroencephalography (EEG) was recorded using the cable-tethered PAL-8200 system (Pinnacle Technology Inc., Lawrence, KA, USA). After anaes-thesia and placement of epidural electrodes, the mice were treated with bu-prenorphine for pain relief and allowed to recover for at least three days prior to EEG recordings. The preamplifier setting was 100x, and the signal was filtered at 40 Hz. The electrodes were placed according to the manufac-turer’s instructions in six holes drilled through the skull to the dura (1.5 mm lateral to the midline, 2 mm anterior, 2 mm posterior, and 5 mm posterior to the Bregma). Three channels were recorded, which included ipsilaterally from the left frontal area and bilaterally from the frontoparietal and occipital areas. Hyponatraemia was induced by intraperitoneal injection of 1-deamino-8-D-arginine vasopressin (DDAVP) at a dose of 0.5 ug/kg and diluted in sterile water equivalent to 7.5% of the body weight, which was a modification of the protocol described by Vajda[88]. For kainic acid treat-ment, mice were intraperitoneally injected with 20 mg/kg kainic acid (P6503, Sigma–Aldrich, Stockholm, Sweden).

Blood analysis Blood analyses were performed immediately post-mortem using an i-Stat® analyser (Abbot, Sweden). Animals were deeply sedated with an overdose of isoflurane and decapitated. Arterial blood from the neck was immediately

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collected in test cartridges (GC8+). Electrolytes in six mice from each treat-ment group were analysed after the experiment.

EEG analysis EEG recordings were scrutinised for spikes or seizure activity, which were defined as single, short events and high-frequency repetitive patterns, respec-tively, with amplitudes that exceeded the background activity by a factor of at least 2. Seizure activity was also considered present for the remainder of the first observation hour for two mice that died during SE in the first hour after KA treatment, but they were excluded from analysis in the observation hour after diazepam treatment.

Patient and data collection (IV) The study was a prospective observational study. Patients with SAH admit-ted to the Neuro-Intensive Care Unit (NICU) at Uppsala University Hospital between July 2015 and July 2016 were consecutively included. The inclu-sion criterion was spontaneous SAH with an aneurysm treated with endovas-cular coiling. Exclusion criteria were surgical treatment of the aneurysm, a previous history of neurological disease including epilepsy and severe trau-matic brain injury.

At admission, patients were evaluated clinically and investigated with CT including CT angiography. The severity of the clinical condition at admis-sion was graded according to Hunt and Hess grading scale[89]. The amount of bleeding in the first CT was graded according to the Fisher scale. Clinical seizures were systematically recorded and considered acute symptomatic if they appeared during the acute phase of the brain insult[2].

The patients were treated with neurointervention within the first 48 hours in order to eliminate the source of bleeding. The rest of the treatment was done according to our NICU protocols for SAH[90]. In summary, uncon-scious patients had artificial ventilation and an external ventricular drainage (EVD) in order to monitor and treat the intracranial pressure (ICP). Sedation was done with propofol and opioids. Nimodipine was administered intrave-nously or in the nasogastric tube.

Delayed cerebral ischemia is used as a clinical diagnosis and was suspect-ed if there was an onset of new focal or global neurologic deficits or strokes not attributable to other causes. In addition to the clinical examination, DCI was also illustrated by methods including TCD, Xenon-CT and MRI.

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EEG monitoring Continuous EEG (cEEG) monitoring was started as soon as possible after admission to the NICU, usually at the insertion of the EVD. Nine scalp disc electrodes (ASYS Healthcare/Neuroline EEG) F3, T3, P3, O1, F4, T4, P4, O2 and Cz were used. The first 72 hours recorded were analysed. Ampli-tude-integrated EEG (aEEG) trend (based on F3, F4, P3, P4) was used for seizure detection and all suspected seizures were verified or falsified using the raw-EEG. Rhythmic or epileptiform activity with spatiotemporal evolu-tion lasting for at least 10 seconds was regarded as electrographic seizure activity[82]. One neurologist made a primary interpretation of the recordings and two neurophysiologists subsequently made a second interpretation of the suspected seizures.

Measurements of NFL and tau Samples of 5 ml CSF were drawn from the EVD at days 4 and 10 after SAH. The samples were mixed, centrifuged and immediately frozen to -800C. NFL and tau protein concentrations were measured using commercial enzyme-linked immunosorbent assays (NF-Light, UmanDiagnostics, Umeå, Sweden and INNOTEST hTAU, Fujurebio, Ghent, Belgium) according to protocols accredited by the Swedish Board for Accreditation and Conformity Assess-ment (SWEDAC). The measurements were performed in one round of ex-periments using one batch of reagents by board-certified laboratory techni-cians who were blinded to clinical data. Intra-assay coefficients of variation were below 10%.

Statistical methods Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated (us-ing proc logistic in SAS 9.2 and 9.3; SAS Institute) for the occurrence of seizures at the different predefined categories of serum sodium and glucose levels.

In paper III, statistical tests were performed in GraphPad Prism©.

In paper IV data was analysed using SAS 9.4 software. Values of mean, median and standard deviation were calculated. Tau ratio was calculated as the ratio tau 10/tau 4. Cox regression analysis was performed using the pre-dictor biomarkers (those included were H&H, ASS, ES, NFL 4, NFL 10, tau4, tau10 and tau ratio). DCI was analysed as a dependent value.

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Ethics The studies (paper I, II, III and IV) were approved by local ethics commit-tees for human and animal research.

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Results

Paper I From the database 363 patients were found to have sodium levels <125 mM. Medical records were reviewed and 11 patients with seizures in conjunction with their hypernatremia were identified. Seizures were the only manifesta-tion of hypernatremia in patients with serum sodium levels > 115 mM. Using 120 – 124 mM as reference odds ratios (95% CI) for having seizures was calculated

Absolute risks for seizures at different levels of hyponatraemia are given in Table 2. The point estimate of the OR increased with decreasing serum sodium levels, although the confidence intervals (CIs) were wide and partly overlapping.

The 11 patients with seizures and hyponatraemia constituted a very heter-ogeneous group. Their clinical characteristics are summarised in Table 3. All had comorbid conditions of different types, and 5 of the 11 had additional metabolic derangements. The patient with seizures at the lowest serum sodi-um level (104 mM) died.

Table 2. Absolute risk and odds ratio (OR) with 95% confidence interval (CI) for having a seizure at different levels of hyponatraemia in relation to serum sodium levels of 120–124 mM Serum sodium (mM)

Patients (n)

With seizure (n)

Absolute risk (95% CI)

OR (95% CI)

120-124 150 1 0.0067 (0.0002–0.0366) Reference 115-119 120 3 0.0252 (0.0052–0.0719) 3.85 (0.40–37.53) 110-114 54 3 0.0536 (0.0112–0.1487) 8.43 (0.859–82.85) <110 39 4 0.1081 (0.0303–0.2542) 18.06 (1.96–166.86)

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Table 3. Clinical characteristics of patients with hyponatraemia

Paper II In total, 388 patients were included in the study. 14 patients had disturbances of consciousness, including 3 patients with seizures (see Table 4).

Most cases were in the category of 0–2 mM glucose. The majority of cas-es experienced coma; a generalised tonic–clonic seizure was observed only when the s-glucose dropped below 2.0 mM (1.2 mM). Two cases with focal seizures were noted: the s-glucose levels in these patients were 2.0 mM and 3.3 mM respectively.

The mean age of patients with neuroglycaemic symptoms was 54 years (range 20–87 years), and the mean age of patients without neuroglycaemic symptoms was 64 years (range 2–95 years).

12 out of 14 patients with neurological symptoms had diabetes mellitus and were treated with insulin alone or in combination with oral antidiabetic drugs. Comorbidity with alcoholism, severe illness such as nephropathy and terminal prostate cancer were contributing factors in the patients with sei-zures.

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Table 4. Clinical characteristics of patients with hypoglycaemia and neurological symptoms

The absolute risk for developing neurological hypoglycaemic symptoms, including coma and seizures, was highest in the category 0–2.0 mM [0.25 CI (0.13–0.41)] (Table 4.). The absolute risks were 0.02 CI (0–0.06) in the cat-egory 2.1–3 mM and 0.01 (0–0.03) in the category 3.1–3.5 mM (see Table 5).

Table 5. Absolute risk with 95% confidence interval (CI) for neurological symp-toms at different s-glucose levels. Category mM

Patients with-out symptoms

n

Patients with symptoms

n

Patients in total

n

Absolute risk

Confidence Interval

0–2.0 30 10 40 0.25 0.13–0.41

2.1–3.0 151 3 154 0.02 0–0.06

3.1–3.5 193 1 194 0.01 0-0.03

Paper III In this paper, we aimed to rapidly decrease the sodium concentrations in animals to approximately 125–130 mmol/L. To this end, an injection of ster-ile water with the addition of dDAVP to an equivalent of 7.5% body weight

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resulted in sodium levels of approximately 125–130 mmol/L over an obser-vation period of three hours. We next induced hyponatraemia and SE during monitoring in a tethered EEG system. The number of high-amplitude epilep-tiform events (spikes) was significantly increased during the second hour after induction in mice with hyponatraemia (Fig 1). In 5/9 hyponatraemic mice, repetitive spiking could be observed. One mouse displayed high-grade seizure behaviour with loss of postural control and died during induction of hyponatraemia.

Two hours after hyponatraemia induction, the mice (eight hyponatraemic and seven controls) were treated with KA (20 mg/kg). The injection rapidly evoked seizure activity in both groups. Next, we quantified the amount of time animals spent with electrographic seizures during the hour after the injection (see Fig 2).

Hyponatraemic mice showed a significantly longer duration with seizure activity than the controls; 2293 ± 270 s vs. 1373 ± 200 s (SEM) (Fig. 3). One hour after kainic acid treatment, diazepam (20 mg/kg) was administered. During the hour following diazepam treatment, hyponatraemic mice also had significantly longer durations of electrographic seizures compared to con-trols; 3113 ± 129 s vs. 2306 ± 181 s (SEM) (Fig. 3). Two mice with hypo-natraemia died during SE after KA treatment, whereas all control animals survived.

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Fig 1. Epileptiform activity during induction of hyponatraemia. (A) Three traces of EEG during induction of hyponatraemia. The top trace shows EEG immediately after injection, and the two lower traces show occurrence of spikes 90 min after injection. (B) Similar recordings from saline-treated mice without spikes. (C) Quan-tification of spikes during induction of hyponatraemia. Hyponatraemic mice (n=8) demonstrated a significantly higher number of spikes compared to saline-treated mice (n=7) during the second hour of observation after injection (**, indicates p <0.01, ANOVA).

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Fig 2. Kainic acid-induced SE. (A and B) Kainic acid-induced seizure activity in both saline (n=7) and hyponatraemic (n=8) mice. The top trace shows EEG immedi-ately after the onset of seizures, and the bottom trace shows EEG at 45 min after injection. (Q) Quantification of seizure activity showed that the latency to seizure onset was very short in both groups of mice and not significantly different, whereas the time spent with electrographic seizure activity during the hour after KA injection was higher in hyponatraemic mice (*indicates p<0.05, t-test). (D) Quantification of seizure activity during the hour after diazepam treatment showed that hyponatraemic mice (n=7) spent significantly longer time in seizures than saline-treated controls (n=7, **indicates p <0.01, t-test).

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Figure 3. Summary of time spent in seizure for each hour during the experiment. Hyponatraemic mice spent more time in seizure during each hour of the experiment. Hyponatraemia had a significant impact on the time in seizure (*indicates p < 0.05, two-way repeated measures ANOVA on all mice that survived all treatment stages).

Following the experiment, the animals were euthanised, and their blood was analysed for electrolyte disturbances. The sodium concentration was reduced in all analysed mice where hyponatraemia had been induced. No significant differences could be detected in the post-mortem concentrations of calcium, potassium, glucose or blood pH (Table 6).

Table 6. Electrolyte and pH after SE-experiment (n=6 per group)

Paper IV 19 consecutive patients (14 women) were included. The mean age was 61 years (range 43-79). Clinical seizures were observed in 6 patients (32%). Electrographic seizures were seen in 1 additional patient (4.5%). 1 patient did not have cEEG because of technical problems and was therefore exclud-ed from the statistical analysis.

The mean CSF concentrations (±SD) of tau4 were 1672±2687 ng/L (range 75-10000 ng/L) and tau10 2950± 3540 ng/L (range 294-12300 ng/L). The mean value for tau ratio was 3.5±2.4 (range 0.34-10.8). The concentra-

Parameter Saline (+SD) Hyponatraemia p-value (t-test)

Sodium (mg/dl) 143 (+0) 130 (+3.5) 0.0002*

Potassium (mg/dl) 4.5 (+1.4) 4.3 (+1.7) 0.84 Glucose (mg/dl) 195 (+59) 184 (+78) 0.80 pH 7.17 (+0.15) 7.15 (+0.15) 0.87

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tions of NFL 4 were 5612±5366 ng/L (range 340-19100 ng/L) and NFL10 18014±17321 ng/L (range 1850-73100). For details concerning each patient, see Table 5.

Delayed cerebral ischemia was observed in seven patients (37%). Four patients (21%) died during the first two months after development of DCI. Sepsis and bacterial meningitis were the most frequent observed complica-tions. Complete clinical data are shown in Table 6.

Cox regression analysis between tau ratio and DCI showed a Hazard ra-tio [HR]=1.33 per point increase in tau ratio, [(CI) 1.055-1.680. p=0.016]. There was no statistically significant association between DCI and any of the other variables (H&H, ASS, ES, NFL4, NFL10, tau4 and tau10), see Table 7.

Table 7. Clinical data on patients with SAH

Abbreviations: Acute Symptomatic Seizure (ASS), Delayed Cerebral Ischemia (DCI), Electrographic Seizure (ES), Fisher grading scale (Fisher), Hunt and Hess grading scale (H&H). Reference values for lumbar CSF NFL; 40–59 years < 890 ng/L > 60 years <1850 ng/L. Reference values for lumbar CSF tau; 18–44 years < 300 ng/L > 45 years <400 ng/L.

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Table 8. Association between clinical parameters, CSF concentrations of biomarkers and DCI. Variable No of counts Hazard Ratio

(95% CI) p-value

ASS 19 1.4 0.72 ES 18 - - H&H 19 0.9 0.90 NFL4 19 1.0 0.61 NFL10 19 1.0 0.89 tau4 19 1.0 0.81 tau10 19 1.0 0.10 tau-ratio 19 1.3 0.01*

A Cox regression model was applied to evaluate the significance of acute symptomatic seizures (ASS), electrographic seizures (ES), Hunt and Hess severity scale (H&H), concentrations of neurofilament light (NFL), tau and tau-ratio and development of delayed cerebral ischemia (DCI).

*p < 0.05.

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Discussion

This thesis was focused on seizures occurring in different dysmetabolic con-ditions e.g. hyponatraemia and hypoglycaemia and in relation to acute SAH. Such seizures are believed to be provoked (e.i. ASS) and have a different prognosis from that of unprovoked seizures. Acute symptomatic seizures reflect the severity of neuronal derangement and often require emergency treatment. Despite its clinical relevance, little attention has been paid in the scientific literature to studies of risk of ASS in dysmetabolic situations and acute brain insults.

Hyponatraemia and risk of seizures The prevalence of hyponatraemia in the emergency department has been reported to be 2.7% - 2.9%[91], [92]. However, only 0.8 % of 1321 hypo-natraemic patients (defined as sodium < 130 mM) had acute symptoms of hyponatraemia in the survey by Hsu and co-workers. Of these, about half had seizures. It has been suggested that ASS are rare manifestations with sodium levels above 120 mM, and that convulsions or coma do not generally occur until serum levels drop to 95-110 mM[93]. However, the ILAE Com-mission on Epidemiology recognised the lack of systematic data on the rela-tionship between metabolic derangements and seizures and suggested arbi-trary cut off limits for metabolic disturbances, for example levels of hypo-natraemia and risk of seizures[2].

Seizures occurring in patients with sodium disorders are usually general-ised tonic-clonic, but focal seizures or other seizure types may be present. Rapidly evolving electrolyte disturbances are more likely to cause seizures than those developing gradually. It is therefore difficult to define absolute levels of cut off values. In this systematic attempt to assess the risk of acute symptomatic seizures in relation to different levels of hyponatraemia we found a gradual increase in risk that corresponded to decreasing serum sodi-um levels rather than a distinct cut off.

Among the patients, 3 of 120 (2.5 %) with serum sodium levels from 115-119 mM had seizures, as did 3 of 54 (5.4 %) with serum sodium of 110-114 mM. Among patients with sodium levels < 110 mM, 11% had seizures. Us-ing serum sodium levels between 120 and 124 mM as a reference, we found

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a gradual increase in risk with falling sodium levels rather than a distinct cut off.

Of the seven patients with seizures at serum sodium < 115 mM, six had other signs of encephalopathy, whereas no other neurological symptoms were noted among the four patients with serum sodium higher than 115 mM. Seizures could thus be the only manifestation of moderate levels of hypo-natraemia. These data could be of crucial importance to clinicians since ac-curate identification of ASS is needed and correction of underlying metabol-ic derangement is important to control seizures and prevent permanent brain damage.

Hypoglycaemia and risk of ASS Although it is recognised that hypoglycaemia may cause neurological symp-toms, only limited epidemiological data are available on the relationship between the incidence of seizures and hypoglycaemia. In our study of hypo-glycaemic patients we identified 388 individuals with glucose values ≤ 3.5 mM and 14 had disturbed consciousness including 3 with seizures. This observation is in line with a publication from a US emergency department, where 125 patients with symptomatic hypoglycaemia were identified. The majority of the patients suffered from impairment of consciousness, and only 9 had seizures. Diabetes mellitus, alcoholism and sepsis, alone or in combi-nation, accounted for 90% of predisposing conditions.

From textbooks and general overviews, we are taught that there are many causes of ASS, and electrolytic and metabolic disorders are believed to ac-count for 9% of all cases. The number of cases that can be specifically at-tributed to hypoglycaemia, however, is unknown. From this study, it is not possible to predict the true risk estimate for seizures induced by hypogly-caemia. However, the risk of seizures at different blood glucose levels seems to be low. The absolute risk for having symptoms was highest in the catego-ry with very low blood sugar levels < 2 mM[26].

This is a finding of potentially great clinical relevance because seizures in the presence of hypoglycaemia are often believed to be ASS. In view of our findings, a thorough diagnostic work-up of patients presenting with seizures in the presence of hypoglycaemia, especially at moderate levels, is justified.

Hyponatraemia and SE Status epilepticus is a feared neurological emergency situation. Hypo-natraemia is a well-known aggravating factor for seizures and is associated with treatment refractoriness. There are several clinical conditions, such as dehydration, renal failure and some antiepileptic drug treatments, which

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might have an impact on development of treatment resistant SE. In a review of 375 adult cases of status epilepticus, 10% had a metabolic disorder as the primary etiology and mortality in this subset of patients was as high as 40%.[94] Still, there is little experimental data on SE in relation to hypo-natraemia. In this thesis we wanted to apply an animal model of SE and sub-ject the animals to acute induced hyponatraemia. We found that hypo-natraemia in itself induced epileptiform activity in the form of interictal spikes and electrographic seizures on EEG. Alterations of electrolyte gradi-ents across cellular membranes exert effects on neuronal excitability and synchronisation, and consequently epileptiform activity. Furthermore, hypo-natraemia aggravated the response to the chemoconvulsant kainic acid and hyponatraemic mice had significantly longer episodes with seizure activity in comparison with non-hyponatraemic mice as measured by EEG. With a growing interest in optimising SE treatment, we believe that relevant pre-clinical models will be important for refining treatment protocols for SE.

Acute symptomatic seizures in SAH Convulsive and non-convulsive seizures are common complications of SAH. The true frequency of NCS is unknown but has been described in 8% to 30%[78, 95] of comatose patients. It has been shown that seizures (clinical and electrographic) independently predict poor outcome after SAH but a significant relation to vasospasm has never been established. In our study we used continuous EEG monitoring for 72 hours early in the disease course and only found one patient with electrographic seizures. Clinical seizures were observed in six patients (32%). Altogether, seizures were noted in 36% of the patients but their presence could not predict impending DCI.

Biomarkers in SAH Subarachnoid haemorrhage has a huge case fatality rate, underscoring the need for prognostic markers that can be used to aid in the identification of patients at high-risk for poor outcome prior to neurological deterioration. Specifically, development of biomarkers for vasospasm has failed. In paper IV we carried out a prospective study to examine CSF concentrations of two potential biomarkers, NFL and tau.

Reports of NFL in relation to SAH and DCI are very scarce in the litera-ture[96]. One study[97] reported a significant increase in CSF NFL in SAH patients with secondary events. In our study, NFL showed an increase in all patients, but we were not able to detect any association between levels of concentrations of NFL and poor outcome with DCI.

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In previous studies[98, 99] it has been shown that SAH was associated with a significant increase of CSF tau measured at days 1 and 2 and that the increase correlated to extent of brain injury and poor clinical outcome. How-ever, a delayed peak preceding the occurrence of clinical vasospasm did not follow this acute peak. We could not confirm these findings. On the contra-ry, there was no correlation between tau at day 4 and severity of SAH. This discrepancy could be attributed to the rather small numbers of patients in both studies and measurements at different time points. Using tau ratio, a factor that may reflect ongoing brain damage and risk of DCI, an increase was noted in a majority of the patients who developed DCI (five out of sev-en) during the first two weeks. We believe that changes in tau levels between days 4 and 10 could thus be a sign of excessive cortical damage related to development of DCI.

However, we could not detect an increase in tau ratio in the patients that developed DCI later than day 12, most probably due to the limitation of sampling time.

The pathophysiologic mechanism underlying DCI is probably multifacto-rial, and is not fully understood. It has long been argued that cerebral vaso-constriction is the major contributing factor. Other additional mechanisms include spreading depression and “early brain damage”, referring to the damage that occurs to the brain in the first 72 hours after the initial bleeding[100]. Although this takes place before the onset of DCI, it seems probable that the physiological changes increase the energy demand and thereby influence the likelihood of secondary complications such as DCI. With this view, a sensitive CSF biomarker for cortical or neuronal damage would be a valuable tool in treatment aimed at avoiding DCI.

Limitations In papers I and II there are limitations inherent to the retrospective epidemio-logic approach. First, although a large database was used, the number of cases with ASS is small and CIs of our estimates are wide and partly over-lapping. Second, the study is based on reviews of medical records from two single centres, and we were not able to confirm the accuracy of clinical data. It is also possible that there is some underreporting of at least subtle seizures, which would have required EEG for accurate diagnosis. However, this would not have affected the comparison between seizure occurrences at dif-ferent levels of hyponatraemia. A further complication is that the patients constituted a heterogonous group with respect to age, comorbidities, aetiolo-gies and other possible metabolic derangements. Finally, in study I we were not able to separate patients who developed metabolic derangements rapidly from those who developed them more gradually. It is well known that the

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speed of development is important for neurological symptoms, since the brain may adapt to low sodium levels that develop slowly.

In paper III it is important to note that this is an animal model of acute hyponatraemia induced by water intoxication, and because the speed of so-dium reduction is important for the increased seizure risk it is likely that our findings are not directly transferable to more chronic forms of hypo-natraemia. As noted in a previous publication[43], intraperitoneal fluid chal-lenges lead to changes in body fluid distribution, which do not occur in more chronic forms of hyponatraemia. Because our aim was to establish a model in which SE with acute hyponatraemia could be studied, this should not be a major concern.

In paper IV the small number of patients restricts the statistical power of the results. Nonetheless there was statistically significant data supporting the hypothesis that increased tau ratio could be a valuable biomarker for DCI. However, verification of the results in a larger cohort is required in order to be able to rely on the clinical utility of this approach. Other restrictions in-clude the presence of comorbidities and the fact that the use of sedatives and antiepileptic medication was not controlled. This most certainly influenced the EEG results and theoretically could have affected levels of NFL and tau. In the literature, however, there are no data on the impact of sedatives or antiepileptic drugs on biomarkers such as NFL and tau. Furthermore, the optimal timing of measuring CSF biomarkers is not fully established. We chose days 4 and 10 since DCI typically appears between 4 and 10 days after SAH, but more frequent sampling might have disclosed important changes.

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Conclusions

! Hyponatraemia and hypoglycaemia, both frequently encountered in clinical practice, are associated with risk of seizures.

! Seizures associated with hyponatraemia are relatively frequent and there is a gradually increased risk with declining sodium levels.

! Seizures may be the only neurological manifestation of hypo-natraemia with serum sodium levels > 115 mM.

! Acute symptomatic seizures in connection with hypoglycaemia are rare events, and other causative explanations must be considered when patients with hypoglycaemia present with seizures.

! Kainic acid-induced status epilepticus (SE) in mice can be used as a model for studies of the treatment of seizures in hyponatraemia.

! Hyponatraemia induces epileptiform activity on EEG in the mouse model of kainic acid-induced SE.

! Hyponatraemia augments status epilepticus in induced SE in mice. ! Acute symptomatic seizures are common in subarachnoid haemor-

rhage (SAH), but their presence does not predict poor outcome with delayed cerebral ischemia (DCI).

! Continuous monitoring of CSF tau concentrations in patients with SAH during intensive care is valuable since high values of tau ratio (tau10/tau4) in the CSF may be associated to impending DCI.

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Future directions

Future large prospective studies will be useful in predicting a more precise risk estimate for seizures related to both hyponatraemia and hypoglycaemia.

Kainic acid-induced SE seems to be a suitable model for future studies of SE under dysmetabolic conditions. The next stage will be to assess how hy-ponatraemia influences treatment with a range of antiepileptic drugs, such as phenytoin, valproic acid, levetiracetam, barbiturates and lacosamide. Fur-thermore, treatment of KA-induced SE will be used for studies of other dysmetabolic conditions, such as hypoglycaemia.

A larger prospective study of concentrations of NFL and tau with extend-ed time points is needed. It would also be of great interest to conduct a long-term follow up of patients who survived the SAH and to correlate outcomes with concentrations of CSF NFL and tau.

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Summary in Swedish/ Populärvetenskaplig sammanfattning

Epilepsi är ett sjukdomstillstånd som innebär en förekomst av återkommande oprovocerade epileptiska anfall. Om anfallen enbart uppträder i omedelbar anslutning till en provocerande faktor faller de i en annan kategori och kallas för provocerade eller akutsymtomatiska anfall. Akutsymtomatiska anfall förekommer bland annat i samband med infektioner och inflammationer i centrala nervsystemet, vid den akuta fasen av skallskador och stroke, samt vid akut intoxikation, abstinens och metabol påverkan.

Det förekommer relativt ofta att personer som enbart haft akutsymtoma-tiska anfall felaktigt får diagnosen epilepsi. Följden kan bli att dessa perso-ner i onödan sätts in på långvarig underhållsbehandling med antiepileptiska läkemedel, vilket sällan är nödvändigt. Prognosen för oprovocerade anfall och akutsymtomatiska anfall skiljer sig åt med avseende på risk för återfall, dödlighet och behandling. Det är därför det essentiellt att identifiera bakom-liggande orsaker i situationer där akuta epileptiska anfall inträffar.

Denna avhandling fokuserar på akutsymtomatiska anfall som uppträder i samband med vanligt förekommande metabola rubbningar samt vid akut strukturell hjärnskada.

Hyponatremi är ett medicinskt tillstånd där natriumhalten i serum är lägre än 135 mmol/L och är den mest frekvent förkommande av alla elektrolyt-rubbningar. Normalt är natriumhalten 135-145 mmol/L.

I det första delarbetet (paper I), som var en retrospektiv studie av ett stort antal patienter med hyponatremi, studerades risken för att få symtomatiska epileptiska anfall. Studien visade att det förelåg en succesivt ökad risk för anfall i samband med sjunkande natriumnivåer. I en grupp av patienter med serum nivåer av natrium mellan 115 och 119 mM, hade 2,5 % anfall, jämfört med 11 % i gruppen som hade nivåer under 110 mM. Majoriteten av patien-ter med natrium mindre än 115 mM och epileptiska anfall, hade också andra tecken på störningar av hjärnfunktionen till skillnad från patienter med hy-ponatremi med värden över 115 mM där anfall var det enda tecknet på störd hjärnfunktion. Epileptiska anfall kan följaktligen vara den enda uppenbara neurologiska manifestation av måttlig hyponatremi.

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I nästa delarbete (paper II) studerades patienter med hypoglykemi som är ett medicinskt tillstånd med låg blodsockerhalt vilket innebär att cellerna inte får tillräckligt med energi. Studien visade att det var relativt få patienter med hypoglykemi som hade epileptiska anfall. Detta kan tyda på att risken för provocerade anfall vid låga blodglukosnivåer är ganska liten. Denna inform-ation är av potentiellt stor klinisk betydelse, eftersom epileptiska anfall vid hypoglykemi ofta förmodas vara akutsymptomatiska. Det är således motive-rat att i kliniska situationer noggrant utreda om det finns andra bakomlig-gande orsaker till epileptiska anfall som inträffar i samband med hypogly-kemi.

Status epileptikus är ett tillstånd med långvariga eller återkommande epi-leptiska anfall som medför en risk för medicinska långtidseffekter. Det finns flera kliniska observationer som visar att hyponatremi i samband med status epileptikus ofta är förenat med terapiresistens. I avhandlingen tredje arbete (paper III) studerades sambandet mellan hyponatremi och status epileptikus i en djurmodell. I studien framkallades epileptiska anfall på möss genom in-jektion av en neurotoxisk aminosyra. Därefter inducerades hyponatremi och samtidigt registrerades elektroencefalografi (EEG) kontinuerligt. Studien visade att hyponatremiska djur hade en ökad frekvens av epileptiform aktivi-tet jämfört med kontroller. Vidare var durationen av status epileptikus signi-fikant längre. Dessa resultat stöder hypotesen att hyponatremi förvärrar status epileptikus och gör det mer svårbehandlat.

Det sista arbetet (paper IV) är en klinisk studie av patienter som behand-lats på en neurointensivvårdsavdelning på grund av akut subaraknoidalblöd-ningar. Syftet var att undersöka om det fanns något samband mellan epilep-tiska anfall, både kliniska och elektrografiska, och vasospasm (delayed cere-bral ischemia, DCI) vilket är den största orsaken till dödlighet och sjuklighet efter subaraknoidalblödningar. Därutöver mättes koncentrationerna av två biomarkörer för nervskada, neurofilament light (NFL) och tau, i ryggmärgs-vätska från patienterna. Resultaten visade att akutsymtomatiska anfall är vanligt förekommande vid subaraknoidalblödningar (36 % av alla patienter) men förekomst av anfall kunde inte säkert korreleras till dålig prognos. Mätning av biomarkören tau vid olika tidpunkter visade att ökad tau kon-centration mellan dag 4 och 10 kan sammanhänga med risk för att utveckla vasospasm. Resultaten kan förhoppningsvis ligga till grund för ytterligare studier av koncentrationer av tau i cerebrospinalvätska hos patienter med subaraknoidalblödningar som övervakas på intensivvårdsavdelningar pga. risk för att utveckla vasospasm.

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Acknowledgement

The completion of this thesis would not have been possible without the sup-port and help from so many people whose names are not all mentioned here. Without your support, knowledge and encouragement, this work would nev-er have been possible.

First of all I would like to express my deep appreciation to my supervisor Eva Kumlien for her endless support, genuine guidance and extreme en-couragement to find solution for all the problems throughout this thesis.

I would also like to thank the following persons:

Co- supervisor Johan Zelano for his kindness, help and support.

My boss Laila Hellgren Johansson for giving me the time to work with this thesis and for encouraging me to finish it.

Professor Torbjörn Tomson who introduced me to this research field and for his clever ideas.

Co-authors professor Elisabeth Ronne-Engström, professor Henrik Zet-terberg, Pavlos Vlachogiannis, Åsa Amandusson and Kristin Elf for val-uable contributions to our last paper.

Professor Anja Smits and professor Ann- Marie Landtblom who have supported and encouraged me and for your kindness.

Charlotta Bergman and Sari Thunberg for all your practical help.

My colleagues at the Department of Neurology for your support and friend-ship.

My friends for all the help and good times.

My parents Hayat and Mamduh, who have given me endless love, right values and guidance in my life.

46

And last but not least, I have the privilege to thank my wife Helena for her endless patience and love, and my sons Mamduh and Ismael who gave me the energy to continue this journey.

Financial support The dissertation project has been made possible by generous grants from the author’s institution (ALF), and the Selander and Thureus foundations.

47

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