Laboratory Diagnosis in Neurology, 1 Ed.

15 Epileptic Seizures

J. Brettschneider, H. Tumani

Importance of Laboratory Analysis

In patients with epilepsy, laboratory analysis can help clarify whether a doubtful event was actually an epileptic seizure or not. CSF analysis in particular can also provide important information about the possible cause of the seizure, especially early on in the diagnostic process when inflammatory or neoplastic diseases of the central nervous system are under consideration. Furthermore, markers of neurodegeneration in CSF and serum may contribute to an understanding of the pathogenesis of epileptic seizures and indicate possible seizure-related damage to neuronal tissue. In a few cases, laboratory tests can help narrow down the location of the epileptic focus.

Markers of Epileptic Seizures


Physiology. Prolactin is a polypeptide synthesized in the anterior hypophyseal lobe. Its secretion follows a circadian rhythm, with a physiological increase during sleep at night and a return to baseline values within about 2 hours after awakening. Normal serum levels during the day are about 700 μU/mL in women and about 500 μU/mL in men (Bauer, 1996). Nuclear regions in the hypothalamus are important regulatory centers for prolactin release. The ventromedial nucleus and the arcuate nucleus of the hypothalamus physiologically inhibit the release of prolactin.

Prolactin level during seizures. An elevated level of serum prolactin during an epileptic seizure might be caused by epileptic discharge involving the hypothalamus region, possibly via efferent fibers of the amygdala and hippocampus (Cragar et al., 2002). The serum prolactin level normalizes about 2 hours after the seizure.

Postictal prolactin level. Various studies have found an immediate postictal increase in prolactin values in about 85% of all patients with generalized tonic-clonic seizures (Table 15.1) and in about 60% of all patients with complex focal seizures. In the latter group, a prolactin increase seems to occur primarily in patients with temporal lobe seizures, less so in patients with frontal lobe seizures—which may be explained by the greater proximity of the temporal lobe to the hypothalamus. For simple focal seizures, postictal prolactin increases have been reported in about 10% of all cases (Cragar et al., 2002).

Pitfalls with Postictally Increased Prolactin Levels

An increase in prolactin has also been described after psychogenic seizures and after syncope. An immediate postictal increase in serum prolactin has been found in about 80% of patients with complex focal seizures and in 60% of patients with syncope (Lusic et al., 1999). Against this background, use of the prolactin serum level to confirm a diagnosis of epileptic seizure seems only justified when the entire diagnostic picture is taken into consideration.

Creatine Kinase

Physiology. The normal values of serum creatine kinase (CK) are 5–55 U/L in men and 5–35 U/L in women.

Postictal levels. In patients with generalized tonic–clonic seizures, serum creatine kinase shows a postictal increase to 8- to 12-fold the normal value; in patients with focal motor seizures, creatine kinase rises to on average 3.5-fold the normal value (Chesson et al., 1983; Wyllie et al., 1985; Table 15.1). The maximum level is usually reached after about 40 hours, and then the values slowly normalize (within about 4 days). It has been shown by electrophoresis that the increase in creatine kinase is almost exclusively due to an increase in the CK-MM isoenzyme from skeletal muscles (Chesson et al., 1983). The increase depends on the extent and intensity of muscle contractions during the epileptic seizure. These contractions possibly cause changes in the sarcolemma, which then persist for 3–8 days and lead to the release of creatine kinase into the extracellular space.

Pitfalls with Creatine Kinase in Epileptic Seizures

Apart from in the context of motor seizures, serum levels of the CK-MM isoenzyme may also rise after physical exertion, during dystrophic, inflammatory, or toxic muscular diseases (e. g., Duchenne's muscular dystrophy, polymyositis, rhabdomyolysis, hyperthermia), and after intramuscular injections or surgery. An increase in creatine kinase is therefore nonspecific and, like serum prolactin levels, may only be used to confirm a diagnosis of seizure when the entire picture is taken into consideration.


Telencephalin, a member of the family of intracellular adhesion molecules (ICAM), appears to confirm a diagnosis of temporal lobe seizures (Table 15.1). Telencephalin levels in serum were found to be significantly elevated in patients with temporal lobe epilepsy and herpes simplex encephalitis as compared to healthy controls or patients with Alzheimer-type dementia, generalized epilepsy, and disseminated encephalomyelitis (Rieckmann et al., 1998).

Table 15.1 Biochemical markers for differentiating between epileptic and nonepileptic seizures





Elevated; does not differentiate between epilepsy and syncope

• Serum, 80% vs. 60% (Lusic et al., 1999)

• Serum, 80% (Tumani et al., 1999)


Lowered during treatment with anticonvulsants

Serum (Wong et al., 2002)

Creatine kinase

Postictal CK increase, maximum after about 40 h, slow normalization within about 4 days

• Serum (Chesson et al., 1983)

• Serum (Wyllie et al., 1985)

Telencephalin (ICAM-5)

Indicator of temporal lobe dysfunction

Serum (Rieckmann et al., 1998)

NSE (indicator of neuronal damage)

• Increased in CSF and/or serum:

– Status epilepticus

– Epileptic seizure

– Nonconvulsive status epilepticus

• Correlates with seizure duration and outcome

• Serum (Rabinowicz et al., 1995)

• CSF (Correale et al., 1998)

• Serum (Büttner et al., 1999)

• Serum (Tumani et al., 1999)

• Animal model, CSF (Hasegawa et al., 2002)


• Unchanged:

– Absence status, febrile seizure (focal > generalized), epileptic seizure

– Epilepsy in children (symptomatic > idiopathic)

• CSF, serum (Shirasaka, 2002)

• CSF, serum (Tanabe et al., 2001)

• CSF (Palmio et al., 2001)

• CSF (Wong et al., 2002)

Hormones (cortisol, ACTH, T3, T4, TSH, LH, FSH, GH)

Postictal increases persist for about 2 h

Motta et al., 2000

Table 15.2 CSF analysis following the first epileptic seizure: possible causes of the disease and CSF findings


Typical findings in CSF and/or serum


Acute inflammatory changes (pleocytosis, barrier dysfunction, synthesis of pathogen-specific antibodies)

Autoimmune encephalitis

Changes suggestive of chronic inflammation (possibly mild pleocytosis, oligoclonal IgG bands)

Paraneoplastic syndrome

Possibly mild pleocytosis and barrier dysfunction, detection of paraneoplastic antibodies (e. g., Hu, Yo, Ri)

Hemorrhage (subarachnoid)


Neoplastic diseases

Possibly pleocytosis and barrier dysfunction, increase in lactate, tumor cells, tumor markers (e. g., CEA)

Causes of Symptomatic Epileptic Seizures

In general, there is a wide spectrum of diseases diagnosable by laboratory analysis that can cause epileptic seizures (Table 15.2):

• Acute inflammatory diseases (meningoencephalitis).

• Chronic inflammatory autoimmune diseases (disseminated encephalomyelitis, CNS vasculitis, Hashimoto's encephalopathy).

• Paraneoplastic or neoplastic diseases (limbic encephalitis, leptomeningeal spread from carcinoma or lymphoma).

For all these cases, the etiology of symptomatic seizures can be explored by laboratory analysis, particularly CSF analysis, but also by blood tests.

Indicators of the Pathogenesis of Seizures

As shown in animal models of epilepsy and in histopathological preparations of resected epileptogenic brain tissues, the epileptic process causes glial activation and neuronal damage in the central nervous system. This may lead to the release of specific marker proteins into the CSF and/or blood, where they can be determined quantitatively.

NSE as a Marker

One of the best studied markers is neuron-specific enolase (NSE). It has been reported that convulsive and nonconvulsive epileptic seizures—serial seizures, status epilepticus, secondary generalized tonic—clonic seizures, complex focal seizures—are associated with a transient rise NSE in both CSF and blood. A correlation between the NSE value and the severity or duration of seizures has been observed (Rabinowicz et al., 1995; Correale et al., 1998; Büttner et al., 1999; Tumani et al., 1999; Palmio et al., 2001; Tanabe et al., 2001; Hasegawa et al., 2002; Shirasaka, 2002). The time interval between seizure and specimen collection is also very important. Figure 15.1 displays the temporal course of serum NSE levels after SGTC seizures and after complex focal seizures. The concentration dynamics show that, on the one hand, only a small fraction (about 30%) of seizures are associated with an increase in NSE; on the other hand, the level is highest immediately after the seizure, although intraindividual fluctuation also seems to be possible (Tumani et al., 1999).


Fig. 15.1 a, b Kinetics of prolactin and NSE after temporal lobe seizures (blue lines) and secondary generalized tonic–clonic seizures (black lines).

a Kinetics of prolactin.

b Kinetics of NSE.

Lateral Localization of Focal Seizures by Presurgical Evaluation

One of the most important uses of CSF markers in epileptology is in the presurgical evaluation of epilepsy, provided the CSF can be collected by foramen ovale puncture (Fig. 15.2). Both neuronal and glial proteins are elevated in the interictal cisternal CSF collected ipsilateral to the focus (e. g., a 10-fold increase in NSE and a 4-fold increase in S 100B) (Steinhoff et al., 1999). Since no unusual structural changes are seen in the MRI, these markers are either a sign of structurally invisible cellular damage or a sign of nonspecific glial cell activation or neuronal stimulation. As control markers derived not from the brain parenchyma but from the plexus and leptomeninges, cystatin C and β-trace protein have been studied. These markers show normal concentrations in the cisternal CSF contralateral and ipsilateral to the epileptogenic focus. The meninges do not seem to be affected by epileptic seizures.


Fig. 15.2 S 100B and NSE concentrations in cisternal CSF after bilateral foramen ovale puncture (ipsilateral and contralateral to dominant side of the seizure) of patients with temporal lobe epilepsy (TLE). Controls: patients with trigeminal neuralgia (TN).


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