Letter to the editor: Cytokines and Epilepsy.
A Clinical Study.
by Ruediger Lorenz
Received:
December 31, 2001
Sir - In this letter I want to comment on my previous communication
about cytokines and epilepsy (1). Though in
parts this commentary may be of anecdotal character, I hope,
it will be 'synthetic research' as defined in this journal (2).
Cytokines
developed in early evolutionary times. So, they interact in
a similar manner in various species whose evolutionary pathways
separated for some 500, 000, 000 years, for example, like in
mytilus edulis and in humans (3).
The
CNS regulates cytokine secretion and cytokines act on the CNS.
Statistical
analysis of my data is not possible, but I have hints that the
hemispheric differences of regulation (1) are
due to dominant/non-dominant - and not to left/right hemisphere.
I have no hints that they reflect a dominant hemisphere's requirement
of a special immunological protection, but I am sure, that the
immune and endocrine system is regulated by the CNS in an antagonistic
but manifold interacting way.
Therefore,
considering the dominant hemisphere's cortex as stimulating
the immune and endocrine system is not of proper exactness.
Interhemispheric connections (4) must be taken
into account. By the way, these interactions do not only relate
to regulation of the cytokine secretion in general, for it has
been found that cytokine secretion inside the CNS reciprocates,
too (I am sure that it is problematic to do a hard cut in this
concern!): Limbic status epilepticus in the rat, induced by
unilateral injection of kainat, leads to enhanced TNFa
secretion in the hippocampi (5). Moreover,
it is of importance as to which function of the immune and endocrine
system is observed. The influence of the subcortical structures
(6) has to be analysed, and, in addition to
that intrahemispheric differentiation must be given attention:
the anterior prefrontal region is of high importance in immunological
concern (4). There are hints in my patients,
too, that especially rostral foci are combined with elevations
of cytokines in the sera.
The
case history of a girl presenting marked left sided frontotemporal
cortical dysplasia with bizarre neurons and balloon cells (histology
by Prof. Lahl, Bethel, Germany) and severe epilepsy gives hints
for the importance of rostral CNS regions in immunological concern.
Before frontotemporal resection combined with subpial dissections
(Dr. Pannek, Bethel) was performed, despite many seizures no
elevations of IL1-concentrations in the serum were found. After
neurosurgical treatment, the girl not only did not present seizures,
but there also was substantial progress concerning development
of language and motoric faculties, demonstrating, that the dysplastic
structures, besides epileptic stimulation, had effected inhibition.
In accord with this, IL1-concentrations now were elevated. These
findings may support the hypothesis, that in this case of severely
altered CNS, there is an impairment of the immune system's stimulation
by the left rostral hemisphere.
The
hypothesis that the left and right hemispheres influence the
immune and endocrine system in different ways is supported by
the observation that women with left temporal epilepsies have
a tendency to have polycystic ovaries (the pathogenesis of which
are excessive secretions of luteinizing hormone with higher
pulse rates than normal), whereas woman with right temporal
epilepsy have a tendency to hypogonadotropic hypogonadism. The
influence of the intrahemispheric localization of the focus
is demonstrated by the fact that in women with non-temporal
rightsided foci polycystic ovaries are also found (7).
There
are hints, that melatonin participates in the network of cytokine
secretion. In a boy suffering from intractable grand mal epilepsy
the frequency of seizures in winter times was higher than in
the summers, which condition could be observed during some years.
It is known that some epileptic patients benefit from therapy
with visible light (8). Light influences secretion
of melatonin and melatonin influences the immune system. I hypothesize,
that these facts partly explain the observations.
Indeed,
propanolol medication did not only lower excretion of 6-sulfamethoxy-melatonin
in the patient's urine (Dr. Olcese, Hamburg) but also the concentrations
of IL1a and IL1b
in the serum. When propanolol was given, they amounted to 4.3
pg/ml resp. 3.9 pg/ml, whereas the mean concentrations (5 samples
were examined), when propanolol was not given, amounted to 6.7
pg/ml resp. 5.8 pg/ml. But, unfortunately, an improvement of
epilepsy was not seen when cytokines were suppressed. The author's
IL1a- and IL1b-concentrations
amounted to 5.8 pg/ml resp. 4.9 pg/ml, when 3 mg melatonin were
given, and to 3.8 pg/ml resp. 3.1 pg/ml, when 10 mg propanolol
were given (drugs were taken in the evening and blood samples
were taken in the morning of the next day). In contradiction
to these findings, in an erethic child suffering from epilepsy
and tuberous sclerosis no differences between the IL1a-
and IL1b-concentrations before and
after beginning the melatonin treatment (6 mg in the evening)
were seen. Melatonin plays an important role in the regulation
of cytokine secretion. But the network of this regulation is
a very complex one with many interconnecting pathways. The rhythmicity
of the system augments this complexity in a dramatic manner
(3).
Naturally, it is an important question, if therapeutic consequences
can be derived from these findings. Cytokines have contrary
effects: they destroy and repair (9), they
can cause synaptic inhibition and excitation by inhibition of
inhibition (10), and so it is difficult, to
derive therapeutical concepts, which are based on influencing
cytokines. But, cytokines are a very important part of epileptogenesis
as is demonstrated by the following finding: whether patients
with temporal lobe epilepsy will develop a sclerosis of the
hippocampus can be dependent of the presence of certain IL1b-polymorphisms
(11). However, other authors could not confirm
these results (12).
An
example demonstrating that the modification of cytokines could
serve as a therapeutic principle in the treatment of epilepsy,
is the following: Mice preinjected with preparations of shigella
dysenteriae, which induce TNFa- and
IL1b production, presented more seizures
after application of pentylenetetrazole than mice preinjected
with saline. If TNFa- and IL1b-antibodies
were applied in the first group additionally, the induction
of seizures was diminished (13).
Another
way could be to influence melatonin itself. I have hints for
my hypothesis, that vagus nerve stimulation acts partly via
melatonin.
Finishing
this commentary, I want to focus on a special condition: coinciding
of epileptic seizures and psychotic symptoms, which can be expression
of epilepsy or psychosis. Literature gives suggestion for the
relevance of IL2 in psychosis: a treatment with IL2 is able
to provoke symptoms of delusion, perturbances of cognition,
and, to a lesser degree, of affects. The diminished production
of IL2 induced by in vitro stimulating the lymphocytes of patients
suffering from schizophrenia is interpreted as a reaction of
exhaustion. Concentrations of IL2 in the cerebrospinal fluids
of untreated schizophrenic patients are higher than those of
controls (literature: see 14).
A
15 years old boy, whose (presumable monocygotic) twin a few
months ago had suffered from a psychotic episode coinciding
with an epileptic seizure, presented symptoms of excitation,
anxiety, uttered the suspicion, that someone would have put
something 'strange' in his beverage, and his sensation of his
own body was changed. Some days later, he suffered from a grand
mal seizure, and, despite treatment with valproate, 5 weeks
later from a second one.
The cytokine findings in the sera were the following:
Laboratory,
methods and normal values are mentioned in (1).
IL2 has been determined in the laboratory of Prof. K. P. Ringel,
Aachen, by the means of enzymeimmunoassay.
Normal values: 0.5 U/ml - 2.5 U/ml.
Normal
values of IL2 coincided with diminished psychotic symptoms.
As values of IL1a and IL1b
furthermore were elevated, when IL2 was in normal ranges, it
seems likely, that the patient suffered from epilepsy and psychosis
as different entities.
In
a 14 years old boy suffering from epilepsy ictual aphasia, EEG-
and NMR-findings suggested left temporal focus. He reported
the feeling to be influenced ("like television without
antenna") and of déjà vue and of jamais vue.
The serum-concentrations of IL1 and IL6 were elevated, whereas
IL2 was in normal ranges. This patient suffered from psychic
aura of epileptic origin, as known in foci situated in the basal
temporal region of language-dominant hemisphere (15).
So:
determinations of cytokines can help to differentiate psychotic
symptoms of epileptic and not epileptic origin.
Conclusions
1.
Cytokines are a very interesting field of theoretical psychoneuroimmunological
research.
2. Analysis of cytokines can be helpful in the treatment of
epileptic patients.
3. In the future, perhaps treatment of epileptic patients based
on modification of cytokines will be possible.
Acknowledgment
I
am much obliged to Dr. Dagmar Dralle, who has introduced me
in the field of neuropediatrics, Prof. Dr. Klaus-Peter Ringel
because of many discussions concerning immunological questions,
Karin Wagener because of very patient writing of my reports.
References
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Lorenz R. Letter to the editor Neuroendocrinology Letters 2001;
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2.
Mess B. "Analytical" or "synthetic" research
in the life sciences
Neuroendocrinology Letters 200; 22:153-154.
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In: Scharrer B, et al, editors. Neuropeptides and immunoregulation.
Springer; pp. 101-119.
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of the Right and Left Cerebral Neocortex in the Modulation of
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11.
Kanemoto K, Kawasaki J, Miyamoto T, Obayashi H, Nishimura M.
Interleukin (IL)-1b, IL-1a,
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12.
Buono RJ, Ferraro TN, O'Connor MJ, Sperling MR, Ryan SG, Scattergood
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