Neurol Sci (2014) 35:983–993

DOI 10.1007/s10072-014-1701-0

REVIEW ARTICLE

Anticonvulsant drugs and hematological disease

A. Verrotti • A. Scaparrotta • S. Grosso •

F. Chiarelli • G. Coppola

Received: 26 November 2013 / Accepted: 24 February 2014 / Published online: 12 March 2014
Ó Springer-Verlag Italia 2014

Abstract Many antiepileptic drugs (AEDs) are associ- Keywords Hematological disorders
Antiepileptic
ated with hematological disorders that range from mild drugs
Pathogenetic mechanisms
Blood dyscrasias
thrombocytopenia or neutropenia to anemia, red cell
aplasia, until bone marrow failure. Fortunately, potentially
fatal hematological disorders such as aplastic anemia are Introduction
very rare. This review investigates hematological effects
associated with classic and newer AEDs: a PubMed search Many antiepileptic drugs (AEDs) are associated with
indexed for MEDLINE was undertaken to identify studies hematological disorders with a spectrum of hematological
in adults, children and animals using the name of all abnormalities that ranges from mild thrombocytopenia or
anticonvulsant drugs combined with the terms ‘‘hemato- neutropenia to anemia, red cell aplasia, until bone marrow
logical disease’’ and ‘‘hematological abnormalities’’ as key failure. Fortunately, potentially fatal hematological disor-
words. The most common hematological alterations occur ders such as aplastic anemia are very rare [1].
with older AEDs than newer. Indeed, careful hematological This review investigates hematological effects associ-
monitoring is needed especially using carbamazepine, ated with classic and newer AEDs and potential pathoge-
phenytoin and valproic acid. The pathogenetic mechanisms netic mechanisms.
are still unknown: they seem to be related to an immuno- A PubMed search indexed for MEDLINE was
logical mechanism, but drugs pharmacokinetics and phar- undertaken to identify studies in adults, children and
macodynamics interactions may also play an important animals using the name of all cited anticonvulsant drugs
role. Further research is needed to assess the real patho- combined with the terms ‘‘hematological disease’’ and
genetic mechanism at the basis of hematological compli- ‘‘hematological abnormalities’’ as key words. The date
cations caused by AEDs. of our last search was February 2013 and the time
period covered was *40 years. English language arti-
cles were reviewed. References of the selected article
were consulted for possible relevant articles. Table 1
A. Verrotti
summarizes the most relevant hematological alterations
Department of Pediatrics, University of Perugia, Perugia, Italy
e-mail: [email protected] associated to classic and newer AEDs analyzed in this
review.
A. Scaparrotta (&)
F. Chiarelli
Department of Pediatrics, University of Chieti, Chieti, Italy
e-mail: [email protected]
Classic antiepileptic drugs
S. Grosso
Department of Pediatrics, University of Siena, Siena, Italy Benzodiazepines
G. Coppola
Department of Child Neuropsychiatry, University of Naples, The most common benzodiazepines (BZP) used are clo-
Naples, Italy nazepam, diazepam and lorazepam, drugs that exert their

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984 Neurol Sci (2014) 35:983–993

Table 1 Hematological alterations associated to classic and newer anticonvulsant drugs

Anticonvulsant drugs Hematological alterations Frequency References

Benzodiazepines Thrombocytopenia, leukopenia, agranulocytosis, pancytopenia, acute Rare [1, 4–9]

granulocytopenia, acute thrombopenic purpura
Carbamazepine Aplastic anemia, agranulocytosis, pancytopenia From 1:38,000 [1, 18, 19,
to 1:10,800 35, 36, 38]
Mild anemia \5 %
Thrombocytopenia, leukopenia, neutropenia Less frequent
Ethosuximide Aplastic anemia, agranulocytosis Extremely rare [40–42]
Phenytoin Thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia, pure red Rare [1, 43–55]
cell aplasia, aplastic anemia, macrocytosis, megaloblastic anemia
Phenobarbital Aplastic anemia, panmyelopathy Rare [1, 62, 63]
Megaloblastic anemia, leukopenia, agranulocytosis, thrombocytopenia Not reported
Primidone Megaloblastic anemia, thrombocytopenia Frequent [60, 68–70]
Valproic acid Thrombocytopenia 5–60 % [1, 13, 71,
Hypofibrinogenemia Frequent 83, 86]
Pancytopenia, neutropenia, leukopenia, bone marrow suppression Rare
Felbamate Aplastic anemia, thrombocytopenia Rare [87, 88]
Gabapentin Neutropenia Very rare [89]
Lamotrigine Thrombocytopenia, agranulocytosis, aplastic anemia, bone marrow depression, Rare [90, 91]
pancytopenia, disseminated intravascular coagulation
Leukopenia, neutropenia More frequent
Levetiracetam Anemia 4.6 % [93–98]
Leukopenia 4.8 %
Ecchymosis 4%
Neutropenia and pancytopenia Not reported
Oxcarbazepine Leukopenia, thrombocytopenia, neutropenia, pancytopenia, hemolytic anemia Rare [100–104]
Topiramate Leukopenia 2.7 % [1, 105–107]
Anemia Rare
Epistaxis 1–4 %
Zonisamide Anemia, immunodeficiency, thrombocytopenia, leukopenia, lymphadenopathy, Rare [1]
microcytic anemia, petechiae, ecchymosis

effect through enhancement of the GABA–benzodiaze- Severe hematological disorders are associated with
pines receptor complex [2, 3]. administration of CBZ, including aplastic anemia, agran-
Severe hematological alterations, e.g., thrombocytope- ulocytosis and pancytopenia, with an estimated incidence
nia, leukopenia, agranulocytosis and pancytopenia are that ranges from 1:38,000 to 1:10,800 according to various
quite rare [1, 4]. studies. Less than 5 % of patients that received CBZ had
There are few and very old case reports of lorazepam presented mild anemia [1].
[5]- and clonazepam [6]-induced pancytopenia, clona- The prevalence of fatal aplastic anemia is slightly under
zepam-induced thrombocytopenia [7] and, finally, of one-treated patients in 50,000, while persistent leukopenia
acute granulocytopenia, acute thrombopenic purpura and occurs in 2 % of patients treated with CBZ [10].
active antiplatelet antibodies during treatment with Several reports described aplastic anemia associated
diazepam [8, 9]. with CBZ use [11]. Although CBZ and phenytoin (PHT)
were associated with aplastic anemia, the International
Carbamazepine Agranulocytosis and Aplastic Anemia Study (IAAAS)
provided insufficient data to evaluate this specific associ-
Carbamazepine (CBZ) is used for treatment of partial sei- ation [12]. Also other authors investigated the frequency of
zures and secondary generalized seizures in adults and serious blood dyscrasias in a cohort study among 29,357
children, acting mainly on voltage-gated sodium channels, patients taking AEDs, found only one case of aplastic
stabilized in their inactivated state [2]. anemia and could not draw specific conclusions with

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respect to the association between use of antiepileptic CBZ, and the bone marrow showed megakaryocytic
agents and this hematological complication [11, 13]. hyperplasia. Recovery was dramatic with platelet count
Yamamoto et al. hypothesized that patients with reduced recovering within 2–5 days of stopping CBZ. In one study,
GSH-Px activity were at a high risk of developing CBZ- the onset of thrombocytopenia within 10 days of initiation
induced hemolytic crisis and/or aplastic crisis, reporting the of CBZ, megakaryocytic hyperplasia, recovery of throm-
case of a 5-year-old boy who developed concurrent intra- bocytopenia within 96 h of stopping CBZ and absence of
vascular hemolytic anemia and erythroblastopenia, proba- further recurrences strongly implicated CBZ as the etio-
bly due to CBZ. Examination of the patient’s and mother’s logical agent [29].
erythrocyte enzyme activities revealed mildly decreased Rarely, agranulocytosis has been described associated
erythrocyte glutathione peroxidase (GSH-Px) activity [14]. with CBZ use [30–32], with an occasionally fatal outcome
Handoko et al. [11] conducted one of the few epide- [33, 34]; it can occur after different periods of exposure, it
miologic studies on aplastic anemia and AEDs’ exposure, is unpredictable, not clearly related to the total dose con-
using data up to 2002, adjusted for confounding by taking sumed and it appears to be an idiosyncratic response. In a
into account comorbidities associated with aplastic anemia non-fatal case, the finding of a positive reaction with an-
and other potentially causal drugs, including the latest tilymphoid leukemia antiserum was seen during the
registrations in the WHO database; they observed that the recovery phase [30].
use of CBZ and valproic acid (VPA) was significantly Transient leukopenia [35, 36] and, less commonly,
associated with aplastic anemia. Isolated cessation of red neutropenia may also occur, especially in patients with a
cell production is a rare adverse effect of CBZ use, low leukocyte or neutrophil count before CBZ treatment.
reported in few cases in adults and children. The pure red However, therapy discontinuation is not indicated unless
cell aplasia developed mostly several months (2–7 months) symptoms are severe, persistent, or accompanied by
after starting CBZ therapy (with daily doses ranging from infections, but meticulous monitoring of blood counts is
150 to 1,000 mg), improving within 10 days of withdrawal, needed, particularly during the first month of therapy,
with complete recovery of all the patients [15]. Other two especially if a hematological abnormality develops and if
cases were reported more recently [16, 17]. the drug is not discontinued. Only when the neutrophil
CBZ-induced thrombocytopenia is also described with count falls below 500/mm3, a severe risk of infection exists
less frequency, developed from 10 to 14 days after initia- [37].
tion [18, 19]: it can be asymptomatic and only detected Leukopenia develops more slowly, in *12 % of chil-
through routine laboratory testing [20, 21] or symptomatic dren and 7 % of adults, within the first 3 months of treat-
and characterized by skin rashes, fever, arthralgia or ment. Leukopenia often reverses, even if CBZ is continued.
swollen joints [10, 22, 23]. The resolution occurs within a White blood cell (WBC) count \3,000/mm3 or neutrophil
few days after stopping CBZ [10, 24, 25]. A systematic count below 1,000/mm3 warrants a decrease in dose with
review of the literature was done [26], with continuous frequent monitoring or discontinuation, if necessary [38].
updates [27], reporting a total of 34 cases of suspected Discontinuation of CBZ should be considered if the
CBZ-induced thrombocytopenia. No definite causal rela- WBC count falls below 2,000/mL, the polymorphonuclear
tionship was established in those cases, with a possible cell (PMN) count falls below 1,000/mL, the erythrocyte
relationship established in some of these [25–27]. Only one count falls below 3.5 9 106/mL, the platelet count falls
previous study had reported CBZ-induced thrombocyto- below 80,000/mL or the hemoglobin concentration falls
penia in which a re-challenge with the drug was performed: below 11 g/dL. These guidelines are applicable for all
a 12-year-old boy with a history of seizures redeveloped AEDs [1].
thrombocytopenia after re-exposure to CBZ, associated It is interesting to note that folic acid can reduce the
with the increase in the levels of platelet-associated IgG development of some blood cell abnormalities linked to
and serum interleukin-6. No plasmatic antibodies against CBZ, having favorable effects on preventing leukopenia
platelet glycoprotein IIb/IIIa or Ib were detected [10]. and drop in hemoglobin in these patients; however, its
Kimura et al. reported that the case of a patient who exact effect and the optimal dose required to enhance its
developed thrombocytopenia during treatment with CBZ, benefits require further investigations [39].
in which lymphocyte stimulation test with CBZ-10, In conclusion, CBZ may exacerbate porphyria, so it
11-epoxide (CBZ-10, 11-EPOX), a major metabolite of should be avoided in these patients [1].
CBZ, was positive, although with CBZ it was negative.
These findings suggest that CBZ-10, 11-EPOX was pos- Ethosuximide
sibly causative in the pathogenesis of CBZ-induced
thrombocytopenia in this case [28]. In most of the reports, This drug reduces the current in the T-type channel on
the onset of thrombocytopenia was 10 days after starting primary afferent neurons that, if activated, causes low-

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986 Neurol Sci (2014) 35:983–993

threshold calcium spikes in thalamic relay neurons that Severe and potentially lethal bone marrow depression
play a role in the spike-and-wave pattern observed during PHT-induced was reported successfully treated with
absence seizures. So, it is mainly used to treat absence intravenous administration of human recombinant granu-
seizure [3]. locyte–macrophage colony-stimulating factor [57].
Aplastic anemia [40, 41] and agranulocytosis [42] are Folate need not to be administered routinely in patients
extremely rare, but potentially fatal hematological altera- receiving PHT, as macrocytosis and megaloblastic anemia
tions caused by ethosuximide (ETS) therapy. Careful are unusual in these patients and because folate has
attention should be given to agranulocytosis that appears potential detrimental effects on plasmatic levels of PHT
1–2 weeks after the start of administration of the drug [42]. and efficacy, causing seizure exacerbations [1, 43]. How-
So, routine monitoring of blood counts during ETS therapy ever, some studies demonstrated that PHT-induced mal-
is useful and should be undertaken [40]. absorption of folic acid, with folate deficiency especially in
children [58].
Phenytoin Also PHT should be avoided in patients with porphyria,
and its use requires caution in patients with hemolytic
PHT is indicated for treating generalized tonic–clonic anemia, because it may rarely cause hemolysis. Methe-
seizures and status epilepticus, playing a major role in moglobinemia has occasionally been reported if overdose
altering sodium ion movements across nerve cell mem- of PHT or in the setting of methemoglobin reductase
branes [2]. deficiency. Although a cause-and-effect relationship has
Serious blood dyscrasias are rare using PHT: it can not been established, there are some reports that described
cause hematological alterations as [1] thrombocytopenia lymphadenopathy including benign lymph node hyperpla-
[43–45], leukopenia, neutropenia, agranulocytosis [46, sia, pseudolymphoma, lymphoma and Hodgkin’s disease in
47], pancytopenia, pure red cell aplasia [48–52], aplastic patients using PHT [1].
anemia [53, 54], macrocytosis and megaloblastic anemia
[55]. Phenobarbital
The reported case of PHT-associated serum-sickness-
like syndrome followed by severe pancytopenia in a Phenobarbital (PB) enhances GABA-mediated increases in
17-year-old female demonstrated (in serum obtained dur- chloride conductance by prolonging the duration of chan-
ing the acute phase) antibodies against homologous nel opening and it is an effective anticonvulsant for many
eosinophils and neutrophils, antibodies against autologous kinds of seizures such as tonic–clonic and focal seizures,
neutrophils, and antibodies to PHT. The serum also and certain clinical epilepsy subsyndromes [2].
inhibited bone marrow granulocyte colon formation Megaloblastic anemia, leukopenia, agranulocytosis and
in vitro. Profound derangements of immunity can be thrombocytopenia can be associated with PB therapy [1].
associated with a PHT-induced serum-sickness-like illness: In 1958, Hawkins and Meynell [59] observed macro-
lymphocyte transformation by pokeweed mitogen was cytosis in as many as 34 % of epileptic patients receiving
impaired and, after recovery, the patient’s lymphocytes PB alone. In the following years, other cases were reported,
were transformed in vitro by PHT addition [56]. also associated with PB use in combination with other
One study tested the hypothesis that adverse hemato- AEDs [60, 61].
logical reactions as aplastic anemia PHT- and CBZ- Aplastic anemia [62] and panmyelopathy [63] were also
induced was due to a defect in detoxification of arene oxide rarely reported, this last one in combined therapy using
drug metabolites [53]. Another study demonstrated, in ETS, PHT and PB in children.
patient with reversible erythroid aplasia PHT-induced, a Animal studies documented multiple organ toxicity,
toxic effect of the drug by specifically inhibiting DNA including hypochromic anemia, following repeated
synthesis in erythroid precursors, probably at the step of administration of PB in rats [64], transient leukopenia,
deoxyrybotide formation [49]. On the other hand, PHT- neutropenia, thrombocytopenia and anemia associated with
induced red cell aplasia is immunologically mediated severe acute PB intoxication in dogs [65], coagulation
through an IgG inhibitor, which requires the presence of defects in cats [66] and secondary thrombocytopenia in a
the drug to suppress erythroid colony formation in vitro rhesus monkey [67].
[50]. PHT-induced agranulocytosis may be explained with
the presence of a non-complement-dependent antibody Primidone
capable of suppressing granulopoiesis, mediating periphe-
ral destruction of polymorphonuclear leukocytes, and Primidone (PRM) is classified as an enzyme-inducing
cross-reacting with a lymphocyte antigen of limited pop- AED: it is not a true barbiturate because it is a desoxy-
ulation distribution [47]. phenobarbital, differing from PB in the absence of the

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carbonyl group in position 2 of the pyrimidine ring, but relevant. The defect is probably localized in a yet-unknown
clinically, it is considered to be in that group [2]. step in hepatic synthesis [71].
Megaloblastic anemia [60, 68, 69] and thrombocytope- There are very few cases reported in adults [73] and
nia [70] are the hematological alterations mostly associated children [74] regarding to deficiency of factor XIII during
with PRM administration. Megaloblastic anemia is caused VPA treatment. The rarity of homozygous factor XIII
by folate deficiency during treatment with PRM, associated deficiency and the return of factor XIII activity to the
with a low dietary intake of folic acid. The anemia is normal range after reduction IN VPA dosage support the
completely reversed by oral supplementation of folic acid. influence of VPA on factor XIII levels.
So, nutritional deficiency is required to precipitate a frank There are not considerable data on VPA-induced
megaloblastic anemia during therapy with AEDs [68], but decrease in vitamin K-dependent coagulation factors,
probably anemia is not due to folic acid deficiency, but to reported occasionally, but the data are not convincing and
interference with the tissue metabolism of folic acid [69]. the pathogenetic mechanism is unclear. However, it is
recommended to check the activities of vitamin K-depen-
Valproic acid dent factors before surgery, if PT and aPTT are patholog-
ical, with consequent orally administration of vitamin K
VPA is a broad-spectrum AED used as the first-line agent [71].
for both generalized and partial seizures. VPA blocks There are very conflicting data on the VPA-induced
voltage-dependent sodium channels, modifies calcium and acquired von Willebrand syndrome (aVWS) in interna-
potassium conductance, increases the activity of the tional literature. Kreuz et al. studied coagulation parame-
GABA-synthetic enzyme glutamic acid decarboxylase and ters in 30 randomized children receiving AEDs, observing:
acts as an inhibitor of GABA transaminase [2]. a reduction in fibrinogen concentration and platelet count; a
VPA-associated impairment of hemostasis has been significant decrease in factor VIII-complex with a decrease
known for about 30 years; however, the clinical relevance in FVIII:C in 33 %, a decrease in von Willebrand factor
of thrombocytopenia, abnormal platelet function, hypofi- (vWF:Ag) in 83 % and in ristocetin-cofactor activity
brinogenemia, and acquired von Willebrand disease type I (vWF:Rcof) in 66 % of the children. The reported inci-
is still unclear and controversial [71]. dence for aVWS was 67 % of patients receiving VPA
Thrombocytopenia occurs in 5–60 % of patients taking therapy. Comparing results with those of a control group
VPA, representing the most common hematological and of a group of patients with congenital von Willebrand
adverse effect of this drug. Children seem to be affected disease (vWD), coagulation parameters in patients with
more frequently than adults, because they are treated more congenital vWD were similar to those receiving AED
often with VPA and frequently with higher doses. Studies therapy. These data suggest the increased tendency to
in pediatric patients showed that children with VPA hemorrhage as VPA-induced vWD [75]. Some authors
monotherapy had a significantly increased blood loss and even excluded alterations involving VWF:Ag, and other
administration of blood products after surgical procedures: studies were not able to reproduce these alterations
the relative risk of an increased blood loss was 23 times involving VWF and FVIII [76, 77].
higher in patients taking VPA than in those without VPA Although these data are conflicting, neuropediatricians
treatment, although no significant difference in bleeding recommend perioperative treatment with desmopressin
times and PT/aPTT was observed. Usually, thrombocyto- [78], which is contraindicated by hematologists [75] who
penia was not severe and without any bleeding symptoms. prefer prophylactic substitution of plasma preparations
Platelets increased within a few days after VPA reduction [79]. Although the prophylactic perioperative treatment is
or discontinuation. Very rare complications reported are recommended, both recommendations are potentially dan-
fatal subarachnoidal bleeding, fatal pulmonary hemorrhage gerous. Between the two recommendations, the perioper-
and pancytopenia [71]. ative treatment of children with VPA-associated aVWS
Although the exact mechanisms of VPA-inducing with VWF containing FVIII concentrate is the best one,
thrombocytopenia are unclear, two possible explanations because desmopressin can promote seizures in these
have been hypothesized: a dose-dependent direct toxic patients [80].
effect on bone marrow production of platelets; and Evaluating thrombophilic effects of VPA, some authors
peripheral platelet destruction due to the formation of observed that it could increase lipoprotein (a) and decrease
autoantibodies against platelets [72]. fibrinogen, which may increase the risk of stroke or other
Another frequent hematological abnormality is VPA- thrombotic events in children. No clinically meaningful
induced hypofibrinogenemia, associated with a low inci- change in the levels or activity of thrombophilic factors
dence of bleeding symptoms and associated with patho- (homocysteine, factor VIII, factor IX, protein C, protein S,
logic PT, aPTT and TT, if decrease in concentration is antithrombin III levels and activated protein C resistance)

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988 Neurol Sci (2014) 35:983–993

was seen; however, these parameters may become clini- principal mechanism of action appears to involve inhibition
cally significant under long-term treatment [81]. Another of voltage-activated sodium channels, resulting in
study observed low protein C and protein S activities in increased inhibition of action potential-firing activity; it
children using VPA, probably caused by VPA-induced also inhibits high-voltage-activated calcium channels that
hepatotoxicity, especially with higher doses [82]. are located presynaptically, and consequently, it inhibits
Mild and transient neutropenia has been reported only in the release of neurotransmitters such as glutamate [2].
isolated pediatric cases [13, 83]. Neutropenia usually Lamotrigine has been associated with rare hematolog-
occurs within the first weeks of drug exposure, resolving ical side effects as thrombocytopenia, agranulocytosis,
within the first days after discontinuing the drug. VPA aplastic anemia, bone marrow depression, pancytopenia
should be discontinued if the absolute neutrophil count and asymptomatic disseminated intravascular coagula-
(ANC) decreases to \500 cells/mm [84, 85]. tion, reported only in a few studies. Several cases of
Mild leukopenia, bone marrow suppression, lymphade- leukopenia and neutropenia have been reported so far.
nopathy and exacerbation of acute intermittent porphyria Risk factors include concomitant use of other AEDs, and
had also been reported [1, 86]. doses exceeding the recommended initial dose or incre-
If an increased bleeding tendency is observed and before ments. However, unknown are the underlying mecha-
surgical procedures, it is very important to assess platelet nisms [90, 91].
count, thrombelastography, PT, aPTT, TT, fibrinogen,
vWF and factor XIII [71]. Hemorrhages, hematomas, Levetiracetam
petechiae, bruising and prolonged bleeding time are indi-
cations for dosage reduction or withdrawal of therapy [1]. Levetiracetam (LEV) is effective in treatment-resistant
partial seizures in adults. It is an enantiomer of the ethyl
analog of piracetam that facilitates cholinergic transmis-
Newer antiepileptic drugs sion, and it has several modes of action: suppression of
negative allosteric modulators of neuronal GABA- and
Felbamate glycine-gated currents; inhibition of voltage-gated calcium
channels; reduction in voltage-operated potassium currents;
Felbamate (FBM) is often effective in seizure disorders and binding to synaptic vesicle protein 2A [2].
refractory to other treatments [87]. It may be an antagonist Although other AEDs have been more convincingly
of the NMDA receptor glycine-binding site, and it may shown to cause thrombocytopenia, very few reports
block the effect of the excitatory amino acids, suppressing described thrombocytopenia induced by LEV [92].
seizure activity. FBM also interact with voltage-dependent Laboratory parameters in patients with refractory epi-
sodium channels and voltage-sensitive calcium current and lepsy remained fairly stable with LEV therapy, with small
enhance GABA-evoked chloride currents [3]. percentages of patients developing anemia (4.6 %), leu-
Very few case reports documented hematological kopenia (4.8 %) or elevated c-glutamyl-transferase levels
abnormalities in patients treated with FBM, especially (5.3 %) [93]. WBC and neutrophil counts were decreased
aplastic anemia [87] and even less thrombocytopenia [88]. in pediatric patients treated with LEV and ecchymosis
occurred in 4 % of treated ones versus 1 % of placebo-
Gabapentin treated patients [94, 95]. No clinically relevant change in
bleeding time or difference from placebo was observed.
Gabapentin (GBP) is used as an adjunctive AED for LEV does not appear to cause clinically significant or
treatment of partial seizure, with or without secondary relevant hematological adverse events suggestive of
generalization, in patients over 12 years of age. It was underlying hematological disorders [96, 97].
formed by adding a cyclohexyl group to GABA, which Also leukopenia, neutropenia and pancytopenia [96, 98]
allowed it to cross the blood–brain barrier. It seems to have with bone marrow suppression have been identified and
an inhibitory effect on voltage-gated calcium channels observed in post-marketing surveillance studies [96].
containing the alpha 2-delta subunit [2]. The English Pharmacovigilance Network of Medicines
Neutropenia is a very rare adverse effect of GBP treatment and Healthcare Products Regulatory Agency reports 41
[89]. There are no reports on other hematological alterations. LEV-related blood disorders, none of these cause the death
of the patient. The most frequent were neutropenia (12
Lamotrigine cases), thrombocytopenia (9 cases), pancytopenia (5 cases)
and leukopenia (4 cases); the less frequent were aplastic
Lamotrigine is used in refractory partial and generalized anemia (2 patients), thrombocytopenic purpura (2 patients),
epilepsies in monotherapy or as an add-on treatment. Its coagulopathy (2 patients), anemia (1 patient), eosinophilia

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(1 patient), lymphopenia (1 patient), bone marrow failure TPM seems to enhance the risks of side effects due to
(1 patient) and idiopathic thrombocytopenic purpura (1 VPA and not described in TPM monotherapy, so caution is
patient) [96]. required [108].
Although no bleeding has been reported with LEV in
clinical studies, one identified, by platelet aggregometry, Zonisamide
that LEV seemed to inhibit thromboxane-dependent
platelet activation and aggregation, with total recovery of Zonisamide (ZNS), 1,2-benzisoxazole compound with a
platelet function observed 3 weeks after treatment substi- sulfonamide side chain, is an effective AED in patients
tution with another molecule. The authors suggest that with refractory partial and generalized tonic–clonic sei-
caution should be exercised when this drug is used con- zures, blocking the repetitive firing of voltage-gated
comitantly with antithrombotic drugs, especially with sodium channels and reducing the T-type calcium channel
antiplatelet agents such as clopidogrel, which do not target currents [2].
the thromboxane A2 pathway, because of an expected Hematological alterations are rarely reported during
additive effect [99]. therapy with ZNS and include the following: anemia,
immunodeficiency, thrombocytopenia, leukopenia, lym-
Oxcarbazepine phadenopathy, microcytic anemia, petechiae and ecchy-
mosis [1].
Oxcarbazepine (OXC) is used in monotherapy or in com-
bination therapy in adults and children with partial and Others newer AEDS
secondarily generalized tonic–clonic seizures. OXC and its
active metabolite, monohydroxy derivative, exert their International literature does not report cases about hema-
effects on sodium channels and probably potassium and tological alterations during treatment with most recent
calcium channels, with a mechanism of action similar to AEDs as lacosamide, rufinamide, eslicarbazepine and
CBZ, with comparable efficacy but superior safety [2]. retigabine.
Although rare adverse effects of OXC therapy, leuko-
penia [100], especially with higher doses, thrombocytope-
nia [101], neutropenia [102], pancytopenia [103] and Pathogenetic mechanisms
hemolytic anemia [104] are reported.
Thrombocytopenia can be caused by increased consumption
Topiramate of platelets (platelet autoantibodies, disseminated intravas-
cular coagulation) or by decreased production; thrombocy-
Topiramate (TPM), a sulfamate-substituted derivative of the topenia itself does not cause a thrombopathy, but at platelet
monosaccharide D-fructose, is an effective drug in reducing counts of \50 9 103/mm3, the measurement of platelet
the frequency of seizures in patients with primary general- function becomes difficult. The most common clinical
ized tonic–clonic seizures, partial seizures or seizures asso- symptoms of low platelet count are petechial bleeding,
ciated with Lennox–Gastaut syndrome as in monotherapy or pathologic platelet-function tests or a prolonged bleeding
as adjunctive therapy. It is considered to exert its action time [71]. The mechanism underlying drug-induced throm-
through the enhancement of GABAergic activity and inhi- bocytopenia seems to be immune related, with the devel-
bition of: kainite/alfa-amino-3-hydroxy-5-methyllisoxazole- opment of drug-dependent antibodies to platelets and
4-proprionic acid-type glutamate receptors; voltage-sensitive secondary platelet destruction. The most commonly targeted
sodium and calcium channels; and most of the carbonic platelet membrane epitomes are the major platelet receptors
anhydrase isozymes (except I and III) [2]. for fibrinogen and von Willebrand factor: the glycoprotein
Hematological diseases as anemia are rare in patients (GP) IIb/IIIa or GPIb/V/IX complexes. As once established,
taking TPM, while, especially in patients with concomitant drug sensitivity probably persists indefinitely, patients
antiplatelet therapy, bleeding tendency may be more evi- should be informed to avoid it constantly [24, 25].
dent. Epistaxis occurs in 1–4 % of them, because TPM Aplastic anemia is a hematopoietic stem-cell disorder
may modulate voltage-gated L-type calcium ion channels characterized by pancytopenia of the peripheral blood and
located on platelets and vascular smooth muscle [1]. hypocellular bone marrow, which requires intensive ther-
TPM gives leukopenia in 2.7 % patients. Its association apy with either bone marrow transplantation or immuno-
with clozapine (that gives leukopenia to 3 % of patients) suppression in its most severe form; case fatality rate is
resulted in death by fulminant septicemia from treatment- *10 % [11, 109]. The pathophysiology of acquired
resistant agranulocytosis. So, frequent laboratoristic mon- aplastic anemia is thought to be immune mediated. Since
itoring is required [105–107]. Palace and Lang [110] hypothesized that autoimmune

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990 Neurol Sci (2014) 35:983–993

mechanisms might have an etiologic role in patients with Indeed, careful hematological monitoring is needed espe-
epilepsy, maybe also results of Handoko et al. could be cially using CBZ, PHT and VPA. The pathogenetic
explained by the underlying disease instead of the AEDs. mechanisms are still unknown: they seem to be related to
However, evidence supporting this hypothesis is not yet an immunological mechanism, but drugs pharmacokinetics
available in literature [11]. and pharmacodynamics interactions may also play an
The neutropenic patient (ANC \1,500 cells/mm3) is important role. Further researches are needed to assess the
highly susceptible to bacterial, fungal and viral infections, real pathogenetic mechanism at the basis of hematological
with the risk of infection associated with the grade and complications caused by AEDs.
duration of the neutropenia, while grade IV neutropenia
(ANC \500 cells/mm3) is associated with a greater risk of Conflict of interest The authors have no financial involvement or
relationship as employment, consultancies, honoraria, stock owner-
infection, regardless of duration. Drug-induced neutropenia ship or options, expert testimony, grants or patents received or
usually occurs within the first weeks of drug exposure and pending, royalties, with any organization or entity with a financial
resolves within the first days after discontinuing the drug. interest in or financial conflict with the subject matter or materials
While it may be safe to continue the medication if the discussed in the manuscript. The manuscript was carefully proofread
and corrected for proper American spelling, grammar and syntax by a
neutropenia is mild, it should be discontinued if the ANC native English speaker.
decreases to \500 cells/mm3 [85]. The pathophysiology of
AEDs-induced neutropenia is still unknown.
The mechanism underlying the erythropoietic suppres-
sion by some AEDs remains to be elucidated. For example, References
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