Abstract

This study presents a rare case of unilateral slipped capital femoral epiphysis treated surgically in a 5-year-old boy with cerebral palsy who was born at 27 weeks’ gestation and developed grade III intraventricular haemorrhage and periventricular leucomalacia and was on antiepileptic drugs, including valproic acid and levetiracetam for >3 years. The patient had no history of endocrine, renal, and significant familial diseases.

Introduction

Slipped capital femoral epiphysis (SCFE) is the most common hip disorder among adolescents. Early and appropriate management can reduce morbidity and complications [1]. The average age of onset of SCFE is 12.7 years for boys and 11.2 years for girls; however, it is rare in children aged <10 years. SCFE has multifactorial risk factors including age, sex, duration of symptoms, race, geographic variation, and seasonal variation, indicating that genetic and environmental factors may play a role in the disease [2]. In addition, the endocrine risk factors, including hypothyroidism, growth hormone administration, renal osteodystrophy, and endocrinopathies [3–8].

Contributory biomechanical factors which may play a role in the disease, such as femoral retroversion, physeal obliquity, and obesity, lead to abnormal stress on the physis and anterolateral displacement of the femoral metaphysis away from the epiphysis [9–12].

This study aimed to describe the case of a 5-year-old independent ambulatory boy with cerebral palsy (CP) treated with antiepileptic drugs (AEDs) who was diagnosed with unilateral unstable SCFE with no endocrinopathies and was treated surgically with percutaneous in situ fixation.

To the best of our knowledge, no similar cases have been reported previously.

Case report

A 5-year-old independent ambulatory Middle Eastern boy with CP who was born preterm and developed grade III intraventricular haemorrhage and periventricular leucomalacia and was on AEDs, including valproic acid (VPA) and levetiracetam (LEV), for >3 years and was controlled over the last year (no history of seizure attack) presented to the emergency room (ER) with right hip pain and inability to bear weight for 4 weeks; the patient had no history of fever or trauma. Physical examination shows a thin, the weight is 12 kg, the height is 101 cm, vital signs within the normal range, tenderness over the right hip, and external rotation of the right hip, with restricted hip mobility. A radiological study was performed ~3 months before the patient presented to the ER for follow-up examination of a left hip coxa valgus deformity with no apparent abnormalities in the right hip (Fig. 1). Initial imaging studies conducted in the ER showed an anterior–posterior view of the pelvic radiograph, revealing Klein’s line [13] not intersecting the capital femoral epiphysis (Fig. 2), and frog-leg lateral view radiograph of the right hip (Fig. 3) confirmed SCFE and Southwick’s slip angle [13] of ~50° (moderate). Laboratory findings were clear for endocrine and renal diseases or infection, except for low vitamin D (total 25-OH Vitamin D: 43.4 nmol/L), suggesting vitamin D insufficiency. The diagnosis was confirmed with clinical and radiological studies as right-sided unstable SCFE requiring surgery. Surgical intervention was performed with percutaneous in situ fixation using a single fully threaded 4.5-mm cannulated screw (Fig. 4). Postsurgical rehabilitation included non-weight-bearing right lower extremities for 6 weeks. Regular follow-up with serial radiology studies showed stable fixation with no migration of screw or further slippage at 6 weeks (Fig. 5) and 3 (Fig. 6), 15 (Fig. 7), and 36 months (Fig. 8). During follow-up, a painless range of motion in the right hip was observed, with full weight-bearing and resumption of his usual activities with no complaints.

Pelvic anterior–posterior radiograph showing coxa valga deformity in the left hip.
Figure 1

Pelvic anterior–posterior radiograph showing coxa valga deformity in the left hip.

Pelvic anterior–posterior radiograph showing SCFE in the right hip, with Klein’s line not intersecting the capital femoral epiphysis
Figure 2

Pelvic anterior–posterior radiograph showing SCFE in the right hip, with Klein’s line not intersecting the capital femoral epiphysis

Pelvic frog-leg lateral view radiograph showing Southwick’s slip angle 50° in the right hip.
Figure 3

Pelvic frog-leg lateral view radiograph showing Southwick’s slip angle 50° in the right hip.

Pelvic anterior–posterior radiograph immediately after in situ fixation with single cannulate screw.
Figure 4

Pelvic anterior–posterior radiograph immediately after in situ fixation with single cannulate screw.

Six weeks following post-operative fixation: (A) pelvic anterior–posterior radiograph and (B) pelvic frog-leg lateral view radiograph.
Figure 5

Six weeks following post-operative fixation: (A) pelvic anterior–posterior radiograph and (B) pelvic frog-leg lateral view radiograph.

Pelvic anterior–posterior radiograph, 3 months following post-operative fixation.
Figure 6

Pelvic anterior–posterior radiograph, 3 months following post-operative fixation.

Pelvic anterior–posterior radiograph, 15 months following post-operative fixation.
Figure 7

Pelvic anterior–posterior radiograph, 15 months following post-operative fixation.

Right hip anterior–posterior radiograph, 36 months following post-operative fixation.
Figure 8

Right hip anterior–posterior radiograph, 36 months following post-operative fixation.

Discussion

SCFE is the most common hip disorder among adolescents in a rapid growth phase [1]. It is rarely affect children aged <10 years. SCFE in this age group is usually due to hypothyroidism, growth hormone administration, renal osteodystrophy, and endocrinopathies [3–8]. There is no known established relationship between incidence of SCFE, epilepsy, and AEDs in the literature. The aim of this study to describe the case of a 5-year-old independent ambulatory boy with CP treated with AEDs who was diagnosed with unilateral unstable SCFE with no endocrinopathies and was treated surgically with percutaneous in situ fixation.

VPA is a broad-spectrum AED used for all types of seizures and syndromes. Its excellent efficacy has been demonstrated over almost 40 years of clinical experience [14, 15]. The mechanism of action of VPA remains unknown, although it has been linked to the blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission [16]. Long-term use of VPA to treat epilepsy in children has been associated with bone weakness and decreased bone mineral density. Although the mechanism underlying this effect is unknown [17–19], studies have shown that paediatric patients who use VPA as a monotherapy for epilepsy have an increased risk of fractures. However, the discontinuation of VPA treatment can reduce the risk of fractures in these patients [20].

Verrotti et al. [21] have revealed that epilepsy and its treatment can affect bone mineralization and calcium metabolism. Various studies have shown a significant reduction in bone mineral density in patients treated with conventional (phenobarbital, carbamazepine, valproate, etc.) and novel (oxcarbazepine, gabapentin) AEDs. Despite data on the possible effects of AEDs on calcium metabolism, the mechanisms underlying these adverse effects remain unknown. Abnormalities in calcium metabolism are believed to result from the cytochrome P450 enzyme-inducing properties of some AEDs and the resultant reduction in vitamin D levels; however, the effect of several medications (e.g. VPA) cannot be readily explained by vitamin D metabolism.

LEV is a second-generation AED that has been on the market since 2000 [22]. Its mechanism of action differs structurally and functionally from other currently available AEDs, as it binds to synaptic vesicle protein 2A (SV2A) [23].

LEV is a safe and well-tolerated novel AED, and no significant drug interactions were noted between LEV and concomitant medications because of lower protein binding and no involvement of hepatic CYP isozymes [24, 25]. It has been suggested that LEV may have no harmful effects on bone strength and metabolism [26–28]. The present study shows that several predisposing factors, such as CP, epilepsy, low vitamin D, and the use of AEDs such as VPA for >3 years, may have led to SCFE. In this study, the patient was not having seizure attacks over the last year, and during the last follow up in clinic (4 weeks before present to the ER) the right hip radiology study showed no obvious hip abnormality. Low vitamin D level might be explained by cytochrome P450 enzyme-inducing properties of some AEDs and the resultant reduction in vitamin D levels as reported earlier. In conclusion, with these predisposing factors, it can’t be linked to any of CP, epilepsy, or AEDs are the cause of SCFE in this patient. Further studies are required to investigate this relationship and to study the histopathological effects of AEDs on proximal femoral bone physis.

Conflict of interest statement

None declared.

Funding

This study was supported via funding from Prince Sattam bin Abdulaziz University project number PSAU/2024/R/1445.

References

1.

Hagglund
G
,
Hannson
LI
,
Sandström
S
.
Slipped capital femoral epiphysis in southern Sweden. Long-term results after nailing/pinning
.
Clin Orthop Relat Res
 
1987
;
217
:
190
200
. https://doi.org/10.1097/00003086-198704000-00017.

2.

Lehmann
CL
,
Arons
RR
,
Loder
RT
, et al.  
The epidemiology of slipped capital femoral epiphysis: an update
.
J Pediatr Orthop
 
2006
;
26
:
286
90
. https://doi.org/10.1097/01.bpo.0000217718.10728.70.

3.

Moorefield
WG
 Jr,
Urbaniak
JR
,
Ogden
WS
, et al.  
Acquired hypothyroidism and slipped capital femoral epiphysis. Report of three cases
.
J Bone Joint Surg Am
 
1976
;
58
:
705
8
. https://doi.org/10.2106/00004623-197658050-00023.

4.

Blethen
SL
,
Rundle
AC
.
Slipped capital femoral epiphysis in children treated with growth hormone. A summary of the National Cooperative Growth Study experience
.
Horm Res
 
1996
;
46
:
113
6
. https://doi.org/10.1159/000185006.

5.

Loder
RT
,
Hensinger
RN
.
Slipped capital femoral epiphysis associated with renal failure osteodystrophy
.
J Pediatr Orthop
 
1997
;
17
:
205
11
. https://doi.org/10.1097/00004694-199703000-00013.

6.

Oppenheim
WL
,
Bowen
RE
,
McDonough
PW
, et al.  
Outcome of slipped capital femoral epiphysis in renal osteodystrophy
.
J Pediatr Orthop
 
2003
;
23
:
169
74
. https://doi.org/10.1097/01241398-200303000-00007.

7.

Bone
LB
,
Roach
JW
,
Ward
WT
, et al.  
Slipped capital femoral epiphysis associated with hyperparathyroidism
.
J Pediatr Orthop
 
1985
;
5
:
589
92
. https://doi.org/10.1097/01241398-198509000-00017.

8.

Heatley
FW
,
Greenwood
RH
,
Boase
DL
.
Slipping of the upper femoral epiphyses in patients with intracranial tumours causing hypopituitarism and chiasmal compression
.
J Bone Joint Surg Br
 
1976
;
58-B
:
169
75
. https://doi.org/10.1302/0301-620X.58B2.932078.

9.

Gelberman
RH
,
Cohen
MS
,
Shaw
BA
, et al.  
The association of femoral retroversion with slipped capital femoral epiphysis
.
J Bone Joint Surg Am
 
1986
;
68
:
1000
7
. https://doi.org/10.2106/00004623-198668070-00006.

10.

Pritchett
JW
,
Perdue
KD
.
Mechanical factors in slipped capital femoral epiphysis
.
J Pediatr Orthop
 
1988
;
8
:
385
8
. https://doi.org/10.1097/01241398-198807000-00001.

11.

Weiner
D
.
Pathogenesis of slipped capital femoral epiphysis: current concepts
.
J Pediatr Orthop B
 
1996
;
5
:
67
73
. https://doi.org/10.1097/01202412-199605020-00002.

12.

Loder
RT
. et al.  
Slipped capital femoral epiphysis
.
Instr Course Lect
 
2008
;
57
:
473
98
. https://doi.org/10.1201/b13489-77.

13.

Samelis
PV
,
Papagrigorakis
E
,
Konstantinou
A-L
, et al.  
Factors affecting outcomes of slipped capital femoral epiphysis
.
Cureus
 
2020
;
12
:
e6883
. https://doi.org/10.7759/cureus.6883.

14.

Pack
AM
,
Morrell
MJ
.
Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications
.
CNS Drugs
 
2001
;
15
:
633
42
. https://doi.org/10.2165/00023210-200115080-00006.

15.

Aldenkamp
A
,
Vigevano
F
,
Arzimanoglou
A
, et al.  
Role of valproate across the ages. Treatment of epilepsy in children
.
Acta Neurol Scand Suppl
 
2006
;
114
:
1
13
. https://doi.org/10.1111/j.1600-0404.2006.00666.x.

16.

Suzuki
Y
,
Itoh
H
,
Abe
T
, et al.  
No effect of co-administered antiepileptic drugs on in-vivo protein binding parameters of valproic acid in patients with epilepsy
.
J Pharm Pharmacol
 
2011
;
63
:
976
81
. https://doi.org/10.1111/j.2042-7158.2011.01282.x.

17.

Sheth
RD
,
Wesolowski
CA
,
Jacob
JC
, et al.  
Effect of carbamazepine and valproate on bone mineral density
.
J Pediatr
 
1995
;
127
:
256
62
. https://doi.org/10.1016/S0022-3476(95)70304-7.

18.

Akin
R
,
Okutan
V
,
Sarici
U
, et al.  
Evaluation of bone mineral density in children receiving antiepileptic drugs
.
Pediatr Neurol
 
1998
;
19
:
129
31
. https://doi.org/10.1016/S0887-8994(98)00039-3.

19.

Kafali
G
,
Erselcan
T
,
Tanzer
F
.
Effect of antiepileptic drugs on bone mineral density in children between ages 6 and 12 years
.
Clin Pediatr
 
1999
;
38
:
93
8
. https://doi.org/10.1177/000992289903800205.

20.

Pavlakis
SG
,
Chusid
RL
,
Roye
DP
, et al.  
Valproate therapy: predisposition to bone fracture?
 
Pediatr Neurol
 
1998
;
19
:
143
4
. https://doi.org/10.1016/S0887-8994(98)00024-1.

21.

Verrotti
A
,
Coppola
G
,
Parisi
P
, et al.  
Bone and calcium metabolism and antiepileptic drugs
.
Clin Neurol Neurosurg
 
2010
;
112
:
1
10
. https://doi.org/10.1016/j.clineuro.2009.10.011.

22.

Rosati
A
,
de Masi
S
,
Guerrini
R
.
Antiepileptic drug treatment in children with epilepsy
.
CNS Drugs
 
2015
;
29
:
847
63
. https://doi.org/10.1007/s40263-015-0281-8.

23.

Lynch
BA
,
Lambeng
N
,
Nocka
K
, et al.  
The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam
.
Proc Natl Acad Sci U S A
 
2004
;
101
:
9861
6
. https://doi.org/10.1073/pnas.0308208101.

24.

Rogawski
MA
.
Brivaracetam: a rational drug discovery success story
.
Br J Pharmacol
 
2008
;
154
:
1555
7
. https://doi.org/10.1038/bjp.2008.221.

25.

Haria
M
,
Balfour
JA
.
Levetiracetam
.
CNS Drugs
 
1997
;
7
:
159
64
. https://doi.org/10.2165/00023210-199707020-00006.

26.

Koo
DL
,
Joo
EY
,
Kim
D
, et al.  
Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy
.
Epilepsy Res
 
2013
;
104
:
134
9
. https://doi.org/10.1016/j.eplepsyres.2012.09.002.

27.

Briggs
DE
,
French
JA
.
Levetiracetam safety profiles and tolerability in epilepsy patients
.
Expert Opin Drug Saf
 
2004
;
3
:
415
24
. https://doi.org/10.1517/14740338.3.5.415.

28.

Di Bonaventura
C
,
Mari
F
,
Fattouch
J
, et al.  
Use of levetiracetam in treating epilepsy associated with other medical conditions
.
Acta Neurol Scand
 
2006
;
113
:
82
6
. https://doi.org/10.1111/j.1600-0404.2005.00554.x.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.