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9 June 2023

Antiseizure Medication-Induced Alopecia: A Literature Review

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1
Medicine Department, Federal University of Santa Maria, Santa Maria 97105-900, Brazil
2
AdventHealth Orlando Neuroscience Institute, 615 E Princeton Street, Suite 540, Orlando, FL 32803, USA
3
AdventHealth Epilepsy at Orlando, 615 E Princeton Street, Suite 540, Orlando, FL 32803, USA
4
Department of Neurology, College of Medicine, University of Illinois, Peoria, IL 61605, USA
Medicines2023, 10(6), 35;https://doi.org/10.3390/medicines10060035
This article belongs to the Section Neurology and Neurologic Diseases
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Abstract

Background: Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported side effects of ASMs. In this context, alopecia is one of the CSEs that has a high intolerance rate leading to poor therapeutical compliance. Methods: We performed a literature review concerning alopecia as a secondary effect of ASMs. Results: There are 1656 individuals reported with ASM-induced alopecia. Valproate (983), lamotrigine (355), and carbamazepine (225) have been extensively reported. Other ASMs associated with alopecia were cenobamate (18), levetiracetam (14), topiramate (13), lacosamide (7), vigabatrin (6), phenobarbital (5), gabapentin (5), phenytoin (4), pregabalin (4), eslicarbazepine (3), brivaracetam (2), clobazam (2), perampanel (2), trimethadione (2), rufinamide (2), zonisamide (2), primidone (1), and tiagabine (1). There were no reports of oxcarbazepine and felbamate with drug-induced alopecia. Hair loss seen with ASMs was diffuse and non-scarring. Telogen effluvium was the most common cause of alopecia. A characteristic feature was the reversibility of alopecia after ASM dose adjustment. Conclusions: Alopecia should be considered one important adverse effect of ASMs. Patients reporting hair loss with ASM therapy should be further investigated, and specialist consultation is recommended.

1. Introduction

The mainstay of treatment for epilepsy is antiseizure medications (ASMs). Approximately 70% of individuals with epilepsy obtain seizure freedom with adequate ASMs therapy [1]. In this context, low literacy levels, high cost, availability, low tolerability, and irregular medication use are some factors related to non-compliance [2]. However, the adverse effects of ASMs remain one of the leading causes of non-adherence. Furthermore, adverse effects can significantly impact the quality of life in people with epilepsy [3]. Cosmetic side effects (CSEs) are the fourth most commonly reported side effect associated with ASMs [4]. Increased body weight, acne vulgaris, hirsutism, and alopecia are some CSEs already reported with ASMs. In a study with 1903 individuals taking commonly used ASMs, weight gain and hair loss were the most common causes of ASMs discontinuation [5]. Additionally, CSEs are estimated to cost around USD 3500 per patient due to therapeutical modifications, consultation costs, and treatment of adverse drug reactions [6]. In addition to the economic burden, CSEs can negatively impact social functioning and emotional well-being and decrease self-esteem and quality of life in epilepsy patients [4].
Alopecia is generally differentiated into cicatricial or scarring alopecia, nonscarring alopecia, and structural hair disorders. In non-scarring alopecia, hair follicle damage is not permanent [7,8]. Non-scarring alopecia is further classified into focal, diffuse, and patterned hair loss [9]. This review will focus on diffuse non-scarring hair loss, the most common type of alopecia found in drug-induced hair loss [10]. The majority of the literature on drug-induced alopecia is related to chemotherapy. Studies assessing the quality of life in individuals undergoing chemotherapy revealed that alopecia ranked amongst the most troublesome side effects affecting body image and was described as distressing [11]. Interestingly, there are no differences between men and women concerning body image regarding the degree of alopecia. However, women’s psychological well-being was lower than men’s because the incidence of alopecia was higher in women [12].
Drug-induced alopecia usually presents as diffuse, non-scarring hair loss commonly reversible upon drug discontinuation [13,14]. Telogen effluvium and anagen effluvium are the two main types of hair loss secondary to medications [15,16]. Anagen effluvium is abrupt hair loss in the anagen phase secondary to impairment of the mitotic or metabolic activity of the hair follicle [17,18]. In this context, anti-neoplastic agents are the most commonly reported drugs associated with anagen effluvium [19,20]. Other medications (bismuth, levodopa, colchicine, and cyclosporine) were rarely reported to cause alopecia [21,22]. Some authors hypothesized that the hair loss probably occurred due to the abrupt cessation of mitotic activity, which can weaken the partially keratinized proximal portion of the hair shaft [23]. This may lead to narrowing and eventual breakage of the hair canal, which can cause complete failure of hair formation. Hair shedding usually begins within the first three weeks of the offending drug. Near complete hair loss is well-established after three months. Interestingly, the scalp is the most common location for hair loss due to its long anagen phase [24].
Telogen effluvium is a common cause of diffuse hair loss [25]. This condition is characterized by hair follicles entering their resting phase (telogen) and falling out too early. People with telogen effluvium can shed more than 100 hairs a day. It usually occurs three months after the introduction of the causative drug. Drugs related to telogen effluvium include anticonvulsants, oral retinoids, oral contraceptives, antithyroid drugs, hypolipidemic drugs, beta-blockers, captopril, and amphetamines [26].
It is believed that the most common antiseizure medications associated with hair loss are valproate and carbamazepine [27]. Additionally, therapies that might improve antiseizure medication-induced alopecia still need to be studied. This study aims to review the literature regarding alopecia and hair loss as secondary effects of ASMs.

2. Methods

2.1. Search Strategy

Primarily, we searched six databases to locate studies on ASM-induced alopecia published in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American & Caribbean Health Sciences Literature (Lilacs), Medline, Scientific Electronic Library Online (Scielo), and Science Direct were searched. Search terms were “alopecia, hair loss, antiepileptic medication, antiseizure medication, epilepsy, and seizure”. During our secondary search [(alopecia) AND (ASM)], we searched for alopecia in 23 ASMs, of which 21 were associated with hair loss (Table 1).
Table 1. FreeText and MeSH search terms in the US National Library of Medicine.

2.2. Inclusion and Exclusion Criteria

Original articles, case reports, case series, letters to editors, and bulletins were included in this review with no language restriction. Google Translate services were used when non-English literature was beyond the authors’ proficiency (Portuguese, English, Spanish, French, and German) or when the abstract in English could not provide enough information. The authors independently screened the titles and abstracts of all papers from the initial search. Disagreements between the authors were resolved through discussion.
All articles discussing at least one ASM causing hair loss were included. Cases where the cause of hair loss was already known and either alopecia did not worsen or was unrelated to ASMs were excluded. Furthermore, cases not accessible by electronic methods, including after a formal request to the authors (by email), were excluded. Patients with more than one contributing factor to alopecia were evaluated using the Naranjo algorithm to estimate the probability of the event occurring.

2.3. Data Extraction

We identified 1680 articles from a primary search. We excluded 1500 articles based on the title and abstract. During our secondary investigation, we identified 151 articles. We included 31 articles from the secondary search. This review included 115 studies containing 1656 individuals (Figure 1).
Figure 1. Flowchart of the screening process.

3. Antiseizure Medications

3.1. Valproate (VPA)

VPA is one of the most frequently used ASMs for treating generalized and focal seizures. It is also indicated for managing bipolar disorders, neuropathic pain, and migraine prophylaxis [28]. VPA is associated with neurological and cosmetic side effects [29]. Alopecia is among the 10 most commonly reported adverse effects of VPA use [30]. The incidence of alopecia secondary to VPA greatly varies from 0.5 to 24% [31]. The diagnosis is based on the history of hair loss or abnormalities following VPA administration. Additionally, it can be confirmed by performing pull tests and modified wash tests.
Hair loss most commonly occurs after three to six months of VPA introduction [32]. Apparently, there is a direct relationship between the occurrence of hair loss and blood levels of VPA. High VPA blood levels (80–150 mcg/L) are associated with alopecia occurrence in 28% of the individuals taking VPA. On the other hand, adequate blood level concentrations (25–50 mcg/L) of VPA are related to a 4 percent occurrence of alopecia [33]. However, a meta-analysis found no significant correlation between the dose or duration of VPA therapy and alopecia [34].
There are five main hypotheses to explain hair loss associated with VPA use [35,36]. The pathophysiology of hair loss includes biotin deficiency, hyperandrogenism, mineral deficiency, telogen effluvium, and vitamin D deficiency (Figure 2) [37,38,39,40,41]. The hair loss associated with VPA is typically incomplete and usually reversible after discontinuing the causative drug [23]. Treatment will include general measures, such as reassurance and hair care techniques. Additionally, some authors reported specific treatment options that should be carefully evaluated case-by-case (Table 2) [35,36,42,43,44,45,46,47,48,49].
Figure 2. Pathophysiology of valproate-induced alopecia. Abbreviations: Cu, copper; Mg, magnesium; VPA, valproate/valproic acid; Zn, zinc [37,38,39,40,41].
Table 2. Management of VPA-associated alopecia by Praharaj et al. [36] adapted by Rissardo et al.

3.2. Carbamazepine (CBZ)

CBZ has a broad use for the treatment of focal seizures. It is also used for treating bipolar disorder and trigeminal neuralgia. Although CBZ is not as notorious for causing alopecia as VPA, the incidence of alopecia with it ranges from 0.3% to 6% [4,50]. In 1985, Shuper et al. reported the first case of CBZ-induced alopecia. An 8.5-year-old girl with headaches and multifocal epilepsy was managed with CBZ. Hair loss stopped after CBZ discontinuation, and hair regrowth was observed [51].
Pillans and Woods reported 177 cases of CBZ-induced alopecia in 1995 [33]. In 1992, Mattson et al. conducted a double-blind trial in 480 individuals with focal seizures and generalized tonic-clonic seizures using VPA or CBZ. Hair loss or abnormal hair texture was observed in 12 percent of subjects taking VPA and 6 percent taking CBZ [52].
In 1997, Ikeda et al. published two individuals that developed hair loss secondary to CBZ therapy. In the first case, the patient was treated for focal epilepsy. Hair loss developed after three months of starting the drug. The blood concentration of CBZ was maintained at 5.0 mg/L. Hair regrowth after replacing the offending drug was observed. The second case reported by Ikeda et al. was an individual diagnosed with tuberous sclerosis with focal seizures. CBZ was started and maintained at a steady level with a blood concentration of 6.5 mg/L. Hair loss was observed after two months of starting CBZ therapy. After reducing the CBZ dose from 600 mg/day to 200 mg/day, hair shedding was reduced, and new hair began to grow [53]. Another case report from Oh et al. demonstrated hair loss four months after starting CBZ at 600 mg/day. The hair loss was reversed after decreasing the dose of CBZ to 200 mg/day [54].

3.3. Lamotrigine (LTG)

LTG is used to treat epilepsy as a monotherapy or as an adjunct to other antiseizure polytherapy. It is a first-line treatment for primary generalized tonic–clonic seizures, focal seizures, atypical absence seizures, myoclonic seizures, and atonic seizures [55]. Apart from using it as an ASM, it can also be used in mood disorders and depression management [56]. The incidence of hair loss associated with LTG is 0.8%. Interestingly, three in every four individuals who developed LTG-induced alopecia reported this side effect as a significant factor for LTG withdrawal [4].
LTG-induced epidermal necrolysis with some hair loss is well known. However, there are few reports of isolated hair loss without epidermal necrolysis associated with LTG in the literature [57]. In 2004, Patrizi et al. reported the first case of LTG-induced alopecia. A 24-year-old female with focal epilepsy was started on LTG and magnesium VPA. The magnesium VPA dose was decreased to 600 mg/day, and the LTG dosage was increased to 100 mg/day. After a few months, hair loss was observed. Trichogram ruled out androgenetic alopecia. LTG probably was the main cause for the development of alopecia, but the effect of VPA on hair structure cannot be excluded [58].
In 2006, Hillemacher et al. reported a case of a 63-year-old diagnosed with bipolar disorder. LTG was started and increased to 150 mg/day. Hair loss was noted in the third week of treatment. A trichogram showed hair with a prolonged telogen phase and dystrophic characteristics [59]. This strongly suggested telogen effluvium as the cause of LTG-induced alopecia. In 2017, Solmi et al. reported a patient affected by treatment-resistant major depressive disorder who was managed with LTG, and telogen effluvium was observed [60].
Tengstrand et al.’s study is one of the most significant articles in the literature regarding LTG-induced alopecia. The authors assessed 337 individuals from 19 countries who developed hair loss associated with LTG. In 291 reports, alopecia developed with LTG monotherapy. They found that alopecia should be considered a significant factor affecting adherence to LTG therapy. The time to onset of alopecia after LTG intake was variable, in which 17 individuals presented alopecia within one month, 48 presented between one and six months, and 31 presented after six months of LTG onset [61]. It is worth mentioning that Tengstrand et al.’s study assessed VigiBase reports, a database with limited information on patient demographic characteristics and clinical descriptions [61].

3.4. Levetiracetam (LEV)

LEV is considered a broad-spectrum ASM. This drug was approved by the FDA in 1999 for the management of epilepsy [62]. Interestingly, LEV differs in structure and mechanism of action from other marketed ASMs [63]. LEV has favorable pharmacokinetics and a low potential for drug interactions [64]. In a study with 1903 individuals, a 0.4% prevalence of hair loss due to LEV therapy was observed [4].
Hair loss is a rare adverse effect of LEV therapy. In 2014, Zou et al. reported five cases of LEV-induced alopecia. The doses of LEV ranged within 500–1000 mg/day. Hair loss secondary to LEV was observed to occur between three and eight weeks of LEV therapy. The individuals presented with diffuse non-scarring hair loss. Complete recovery from alopecia was seen in two out of five subjects. The other two patients noticed an improvement in hair loss after decreasing the dose from 1000 mg/day to 750 mg/day. One individual decided to continue with medication despite hair loss [65]. The authors concluded that the alopecia associated with LEV was due to telogen effluvium. Aghamollaii et al. published a case series of three patients that experienced hair loss with LEV [66].

3.5. Gabapentin (GBP)

GBP is associated with mild adverse events, such as somnolence, fatigue, ataxia, and dizziness, which are reported in about three in every four patients [67]. It is a first-line treatment for the management of neuropathic pain [68]. Eker et al. reported a case of alopecia with GBP therapy for neuropathic pain. The patient was started on GBP 1800 mg/day. Hair loss was noticed one week after the GBP therapy onset. Patchy areas of alopecia were noticed. When GBP was discontinued, hair regrowth was observed [69].
The first case of GBP-induced alopecia was reported in 1997 by Picard et al. A 15-year-old girl with seizures was taking CBZ and phenytoin. GBP 1800 mg/day was prescribed as add-on therapy. The patient experienced alopecia during the second month of treatment with GBP. Hair loss was diffuse without bald patches. GBP was discontinued, but CBZ and phenytoin were continued. Hair regrowth was observed three weeks after GBP discontinuation, and alopecia was completely reversed within one month [70].

3.6. Topiramate (TPM)

TPM may cause alopecia in approximately one percent of its users [8]. According to Chen et al., alopecia prevalence was 1.7% among 230 TPM users. TPM was discontinued in all the individuals who developed alopecia because the patients decided to stop the treatment [4]. Chuang et al. reported a 15-year-old girl with frontal lobe epilepsy who developed hair loss after two months of TPM adjunctive therapy. The hair loss was reversible upon discontinuation of the drug. There was a recurrence of alopecia after the TPM rechallenge [71]. Another case report demonstrated hair loss that started after three months of starting TPM at a dosage of 50 mg/day for migraine headaches. Hair started regrowing with a dose reduction to 25 mg/day, and alopecia recurred after the reintroduction of a 50 mg/day dosage of TPM [72].
Lagrand et al. described a case of an individual who developed alopecia with different medications for managing her tremor-dominant Parkinson’s disease. She presented hair loss after the introduction, in different moments, of levodopa/benserazide, propranolol, and TPM [73]. Their case is interesting because it suggests a possible genetic predisposition for the development of alopecia after the administration of determined groups of medications.

3.7. Phenytoin (PHT)

As part of the Columbia and Yale ASM Database Project, Chen et al. reviewed patient records, including demographics, medical history, ASM use, and side effects for 1903 adult patients (≥16 years of age) newly started on an ASM. Cosmetic side effects were determined by patient or physician reports in the medical record, including acne, gingival hyperplasia, hair loss, hirsutism, and weight gain. PHT was taken by 404 out of 1903 patients. In total, 0.3% attributed hair loss due to PHT and 0.3% intolerability due to hair loss [4]. Herranz et al. assessed the clinical side effects of long-term monotherapy of phenobarbital, primidone, PHT, CBZ, and VPA in 392 pediatric individuals. PHT was more commonly associated with cosmetic side effects than the other investigated drugs. However, there was no report of PHT-induced alopecia. Instead, hirsutism was observed in 9% of children taking PHT [74]. Interestingly, VPA was the drug most commonly associated with alopecia, which occurred in 0.8% of children [75].
Kuhne et al. described a case of Munchausen by proxy syndrome mimicking childhood-onset systemic lupus erythematosus. A patient presenting with malar rash, photosensitivity, alopecia, arthralgia, arterial hypertension, macroscopic hematuria, seizure, and positive antinuclear antibodies was reported. The pediatric patient received high doses of PHT, which led to drug-induced lupus erythematosus [76]. Thus, subjects presenting with alopecia during PHT therapy should be assessed for other clinical manifestations suggesting autoimmune diseases. There are two other cases in the literature with alopecia secondary to PHT-induced lupus erythematosus [77,78].
Hirsutism is more frequent than alopecia as an adverse effect of PHT [75]. In this context, a study assessed the effectiveness of PHT in suppressing chemotherapy-induced hair loss. The authors revealed that oral PHT could significantly suppress hair loss due to cyclophosphamide therapy in rats. PHT co-administration was related to improved hair growth, increased hair-shaft thickness, and reduced skin lipid peroxidation [79].

3.8. Pregabalin (PGB)

Isolated alopecia secondary to PGB was uncommonly described in the literature. Chen et al. found only one patient who developed alopecia among 143 PGB users [4]. In another study with the Netherlands Pharmacovigilance Centre Lareb data, the incidence of PGB-induced alopecia was 0.07% [80]. Noteworthily, PGB dose may be directly associated with hair loss. In Wistar rats, alopecia was more frequently observed with higher doses of PGB [81].
Turgut et al. reported an adult female diagnosed with fibromyalgia. PGB 75 mg/day was started, and the dose was increased to 150 mg/day after one week. Within three weeks of PGB therapy, significant hair loss was observed. PGB was discontinued. Complete hair regrowth was observed after two weeks of PGB withdrawal [82].
In clinical practice, PGB-induced alopecia is commonly seen as part of drug reactions with eosinophilia and systemic symptoms (DRESS). However, it was scarcely reported in the literature. Suh et al. described an individual presenting with alopecia and pruritic erythema after PGB use. DRESS diagnosis was made. After PGB discontinuation, hair regrowth was observed [83].

3.9. Perampanel (PMP)

PMP has been approved as an add-on treatment for refractory focal seizures and primary generalized tonic–clonic seizures in idiopathic generalized epilepsy [84]. The most frequently reported side effects are dizziness and fatigue. In this context, the only described CSE were weight gain (7.4–19.2%) and skin rash (10.6%) [85,86,87]. It is worth mentioning that these CSEs were only observed in specific populations, such as Asian individuals [87].
Rohracher et al. pooled observational data of PMP comprising a full analysis set of 2396 individuals. Only one individual reported alopecia during the first year of PMP therapy [88]. Villanueva et al. assessed the safety and efficacy of long-term PMP in 464 subjects. The incidence of PMP-induced alopecia was 0.2% [89].
The mechanism of action of PMP involves a non-competitive antagonism of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. The AMPA receptors are considered the major subtype of ionotropic glutamate receptors [90]. Noteworthy glutamate can promote hair growth in mice models. Additionally, it is believed that glutamic acid can control hair follicle proliferation, decreasing gene expression related to apoptosis in the skin and increasing cell viability and proliferation in human keratinocytes [91]. Therefore, the low levels of glutamate in PMP therapy may be associated with hair loss.

3.10. Phenobarbital, Vigabatrin, Tiagabine, and Trimethadione

Phenobarbital-induced isolated alopecia was rarely described. Alopecia was usually described as part of an anticonvulsant hypersensitivity syndrome induced by phenobarbital. Huang et al. reported an individual presenting with alopecia in the convalescent status of phenobarbital-induced anticonvulsant hypersensitivity syndrome. Skin histology revealed peri-follicular, peri-bulbar, and supra-bulbar lymphocyte infiltration [92]. In the literature, two other cases of alopecia were present in the convalescent period of phenobarbital hypersensitivity syndrome [93,94]. All individuals reported they had a favorable prognosis with complete hair regrowth within three months [92,93,94]. Huang et al. proposed that phenobarbital could promote lymphocyte infiltration into the peri-follicular, peri-bulbar, and supra-bulbar anatomical regions. Additionally, phenobarbital dose may be associated with the incidence of alopecia. Ghorani-Azam et al. systematically reviewed the literature concerning phenobarbital in neonates and pediatrics that were treated for seizures. Interestingly, alopecia was a reported sign of phenobarbital poisoning [95].
Vigabatrin has also been reported to cause hair loss. In Lampl et al., 5 out of 52 patients who received vigabatrin for focal seizures experienced moderate hair loss or changes in hair structure. The complaints began after three to seven weeks of initiating vigabatrin treatment. Hair loss recovery was seen in all patients after cessation of treatment [96]. Vigabatrin showed different results in rodent studies. It was observed that mice tolerated high doses of vigabatrin, but Sprague Dawley rats developed acute alopecia and body weight gain. These CSEs were improved within six months of vigabatrin discontinuation [97].
Tiagabine may increase the level of γ-aminobutyric acid. Vossler et al. assessed the adverse effects of long-term tiagabine use in 292 subjects. Only one patient developed alopecia secondary to tiagabine [98]. Another study by Mercke et al. found an incidence of 1% of tiagabine-induced alopecia [8].
Trimethadione is historically important for managing absence seizures and refractory temporal lobe epilepsy. There are some case reports in the literature about alopecia associated with this medication [99].
For further description of the cases reported in the literature about alopecia secondary to antiseizure medication, refer to Table 3. Table 4 shows the results from PubMed, cases encountered in the literature, and incidence of ASM-induced alopecia.
Table 3. Literature review of antiseizure medication-induced alopecia.
Table 4. Summary of antiseizure medication-induced alopecia.

4. Discussion

VPA, CBZ, and LTG were the most studied causes of ASM-induced alopecia. Additionally, LEV, TPM, and cenobamate were uncommonly associated with hair loss. However, the rest of the anticonvulsants were rarely reported with alopecia in the literature. To the author’s knowledge, there were no cases of oxcarbazepine and felbamate affecting hair growth. Interestingly, alopecia was usually seen with higher than the usual therapeutic doses of many ASMs [66]. However, there is no established dose-dependent relationship, and in a few cases, hair loss occurred at lower doses of ASM [106].
In most cases reported, hair loss stopped after dose adjustment of the ASM, which included discontinuing the drug or decreasing its dose [70]. In many cases, hair loss recured after ASM reintroduction or an increased dose of ASM back to the original strength that caused alopecia in the first place [72]. Nevertheless, the reversibility of alopecia has been seen as a characteristic feature in all ASMs [73]. Noteworthily, the optimal therapeutic dosage of antiseizure medications should be carefully assessed, especially in individuals with multiple comorbidities due to the modified pharmacokinetics and pharmacodynamics of drugs, which can lead to high percentages of adverse events [172].
The time duration has also been variable in the examples mentioned in this review. The most common duration from starting the drug or increasing the dosage to the onset of hair loss was between one and six months. However, it can vary with the different drugs and their doses. We have mentioned different timelines and associated doses at which hair loss was reported in Table 2. Moreover, hair loss etiology probably was related to telogen effluvium due to features such as non-scarring diffuse distribution, time of alopecia onset, and reversible nature of hair loss. Other than one case, anagen effluvium was not associated with the main cause of ASM-induced alopecia [116].
Telogen effluvium can be diagnosed by identifying known triggers from the history in the three to four months preceding the onset of hair shedding. Additionally, endocrine, nutritional, and autoimmune etiologies should be ruled out. Usually, the diagnosis of telogen effluvium was made by demonstrating a compatible chronology of ASM exposure and onset of hair loss. Hair regrowth within three months of ASM discontinuation can support diagnosis. A drug rechallenge was attempted in some individuals with a re-occurrence of hair loss [43].
Further tests to diagnose telogen effluvium are a hair pull test, 60-second timed hair count, trichogram, trichoscopy, and scalp biopsy [173]. A scalp biopsy can be conducted to identify the earliest stages of androgenetic alopecia, which was already reported with VPA [163]. However, in almost all the studies we analyzed, history was sufficient to label telogen effluvium [174]. A trichogram was performed in only a few reported cases [115,116].
The hair pull test is strongly positive for telogen effluvium [175]. It is carried out by grasping 40–60 closely grouped scalp hair with the thumb and index finger, and gentle traction is applied as the hair is pulled firmly and slowly from the scalp. Normally, only two to three hairs come out. In telogen effluvium, more than 10 percent of hair is easily pulled out from any part of the scalp [176].
In telogen effluvium, the average number of scalp hairs shed daily ranges from 30 to 100, although there is a seasonal fluctuation with the greatest loss around late summer [177,178]. Inspection of telogen hairs with the naked eye can distinguish anagen from telogen hairs [179]. Telogen hairs have depigmented hair bulbs and the absence of inner root sheaths, whereas anagen hairs have inner root sheaths [180]. The inner root sheath can be subdivided into three layers, the cuticle, Huxley’s, and outer Henle’s layers.
Trichogram can help in telogen effluvium diagnosis. Trichogram from a hair pluck sample usually shows more than 25 percent telogen hair in acute telogen effluvium [181]. A 60-s timed hair count can also be performed. Usually, more than 100 hairs will be observed with telogen effluvium (the normal value is 10 hairs) [182]. Another method, which involves combing the air forward for 60 s over a contrasting cloth before shampooing, can be used to assess the disease progression and resolution [183].
An interesting association between hair loss and ASMs is blood zinc concentrations. Low blood zinc levels have been reported in association with higher levels of LEV, especially in cases with reported hair loss [66]. In their letter to the editor, Calabro et al. discussed the relationship between LEV and blood zinc levels. They described a case of a 35-year-old female who was started on LEV and titrated up to 1500 mg/day for generalized tonic–clonic seizures. In the second month’s follow-up, she noticed patchy alopecia. Her zinc levels were below normal (45 μg/dL). Six weeks after LEV discontinuation, hair regrowth was noted. At a one-year follow-up, serum zinc levels were back to normal [106]. Another reported case showed borderline low normal zinc levels one year after stopping LEV due to LEV-induced alopecia [107]. Zou et al. reported that zinc supplementation effectively treated LEV-induced alopecia in five individuals [65]. In this context, Aghamollai et al. prescribed zinc sulfate supplementation for managing hair loss due to LEV. The authors described three patients with alopecia secondary to LEV for whom zinc sulfate 220 mg/day was started. In all three cases, hair loss improvement was seen [66].
VPA-induced alopecia has also been linked with abnormal concentrations of zinc. It has been suggested that low zinc levels may occur due to VPA-induced zinc chelation [184]. However, evidence has shown variable results of zinc blood levels in VPA-treated patients [8]. In animal models, VPA has been shown to induce zinc and selenium deficiencies [44,185,186]. Suzuki et al. showed that long-term ASM therapy, including VPA and CBZ, can decrease zinc levels in the male sex. Interestingly, increased copper concentrations were found in the female sex with long-term ASM therapy [187]. In this context, Kuzuya et al. demonstrated no change in serum zinc or copper levels in patients with epilepsy who had undergone one month of VPA therapy [188]. Therefore, we hypothesize that ASMs can lead to abnormal concentrations of some metals by influencing the absorption of these substances. This can partially explain the development of abnormal levels of zinc and copper with chronic instead of acute ASM therapy.
Zinc and selenium supplementations were already prescribed for VPA-induced alopecia. Fatemi et al. reported an individual with refractory bipolar disorder who developed alopecia secondary to VPA, leading to drug discontinuation. A VPA therapy rechallenge was attempted with zinc and selenium supplementation. There was no occurrence of any hair structural abnormality [44]. Asadi–Pooya systematically reviewed the literature regarding the cosmetic adverse effects of antiseizure medications. They found strong evidence of ASM associated with cosmetic adverse effects. PHT was extensively reported to cause gingival hyperplasia, hirsutism, and acne. VPA was related to causing hair loss and hirsutism. Additionally, they suggest that the evidence for zinc or biotin supplementation in VPA and LEV-associated alopecia needs to be further assessed [189].
There are important limitations in the present study that should be discussed. First, the data in the literature regarding alopecia secondary to antiseizure medication are diverse and sometimes even contradictory. Second, different types of studies with different outcomes to provide an overall view of the literature were included. Third, a significant number of reports only observed alopecia as a secondary outcome, which can affect the incidence of alopecia throughout the studies. Fourth, the majority of the reports of management were about valproate-induced alopecia, but these reports were isolated and had a low level of evidence.

5. Future Perspectives

Future studies with ASMs should assess hair abnormalities with a trichogram. Observing hair structures is essential for diagnosing telogen effluvium. Special attention should be paid to those ASMs whose hair abnormalities were already noted in animal studies. Additionally, the complaints by the individuals in clinical trials with ASM should be further assessed. A mild report of hair loss with ASM should be investigated, and the patient should be recommended to a specialist. Moreover, clinical trials with the supplementation of metal and vitamins in ASM-induced alopecia are important. The development of strong evidence with different treatment options can improve the quality of life and management in people with epilepsy, mainly in those seizure-free individuals with specific types of medications, in which a small dose adjustment can lead to the development of new seizures.
Interestingly, most reports in the literature only described hair loss as a secondary objective of antiseizure medication. Noteworthily, only primary objectives are considered significant due to statistical power. Therefore, future studies need to investigate alopecia as a primary objective of hair loss for further epidemiological assessment and causality. Moreover, most studies describing the management of ASM-induced alopecia are case reports, which can significantly impact the evidence of therapeutic choice.
Understanding ASM’s interaction with genes to cause adverse effects is also important. Pharmacogenomic studies can provide crucial information regarding the potential adverse reactions that the patient may develop with the use of specific medication. These studies are mandatory in individuals with ASM-induced alopecia because there is a significantly higher incidence of VPA-induced alopecia in European and American populations when compared to Asian individuals.

6. Conclusions

Drug-related hair loss is challenging to diagnose. It requires an understanding of normal hair growth and the different causal factors that are involved in it. In this context, hair loss is an important adverse effect of ASM because it affects a significant percentage of the population. Additionally, it can negatively impact the quality of life of people with epilepsy leading to poor therapeutical adherence and a high economic burden. VPA, LEV, and LTG-associated alopecia were extensively reported in the literature. Management of alopecia includes reassurance, hair care techniques, and drug modification. The most frequent management was ASM discontinuation. In some cases, ASM dose reduction was attempted. Hair loss secondary to ASMs was reversible. Metals and vitamin supplementations in the management of ASM-induced alopecia should be investigated.

Author Contributions

J.P.R., A.L.F.C., M.C., H.J.S. and U.H. conceptualized and designed the methodology of the literature review; J.P.R. and U.H. extracted and collected the relevant information and drafted the manuscript; H.J.S. and H.J.S. supervised the article selection and reviewed and edited the manuscript; J.P.R., A.L.F.C., M.C., H.J.S. and U.H. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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