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Flexion contractures of the legs as the manifestation of secondary adrenal insufficiency due to Sheehan’s syndrome
J Orthop Sci DOI 10.1007/s00776-012-0310-0
CASE REPORT
Flexion contractures of the legs as the manifestation of secondary adrenal insufficiency due to Sheehan’s syndrome Masahiko Ikeuchi • Masashi Izumi • Tatsunori Ikemoto • Toshikazu Tani
Received: 7 May 2012 / Accepted: 24 August 2012 Ó The Japanese Orthopaedic Association 2012
Introduction Sheehan’s syndrome (SS) is postpartum hypopituitarism caused by necrosis of the pituitary gland following severe obstetric hemorrhage [1]. Advances in obstetric care have greatly reduced the frequency of SS, particularly in developed countries. The syndrome generally initially manifests as lactation failure, followed by failure to resume menses, and genital hair loss [2]. Herein, we report a rare case of SS presenting with flexion contractures of the legs 20 years after delivery. Consent for the publication of this case was obtained from the patient.
Case report A 53-year-old woman presented with flexion contractures of the legs (Fig. 1). She was unable to walk and used a wheelchair. Two years prior to her visit to our clinic, she felt pain and stiffness in her knees and hips. After a while she noticed that she was unable to fully extend her knees and hips, and then flexion contractures of her legs gradually developed. On admission, she was alert and oriented. Painful flexion contractures were observed in the hips and knees (Table 1). Nevertheless, radiographs showed no obvious abnormalities except for the flexed positions of the hips and knees (Fig. 2). No major joint problem with her upper extremities was observed. Her body height and weight
M. Ikeuchi (&) M. Izumi T. Ikemoto T. Tani Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan e-mail: [email protected]
were 141 cm and 52 kg, respectively. The physical findings for her neck, chest, and abdomen were unremarkable. No neurological abnormalities were detected. Laboratory examination showed normocytic anemia, mild elevation of serum GOT, LDH, CPK, and T-Cho (Table 2). No particular isozyme pattern of CPK and LDH was noted. The results of a nerve conduction study and electromyography (EMG) were unremarkable. Muscle biopsy of the rectus femoris showed no specific findings suggesting myopathies. Autoimmune serological markers associated with rheumatic diseases were negative. Although the serum sodium was normal on admission, repeated laboratory examination showed a remarkable decrease in serum sodium from 136 to 113 mmol/l within two weeks. Her fasting plasma glucose was normal. After consultation with a physician, an endocrinological examination was performed. The results revealed that she had panhypopituitarism (Table 2). Anti-pituitary antibody was negative. MRI of her brain showed atrophy of her pituitary gland with a completely empty sella (Fig. 3). A later interview revealed that she suffered severe hemorrhage (approximately 3000 ml of blood lost) at her fourth delivery, resulting in severe shock when she was 33 year old, and total hysterectomy was carried out. She had already experienced breastfeeding problems and changed it to formula feeding with the third child. Therefore, she did not complain of lactation failure after her fourth delivery. Based on her past history, laboratory findings for her pituitary function, and a lack of specific findings on radiographs, EMG, and muscle biopsy, a diagnosis of panhypopituitarism caused by SS was made. Cortisol replacement therapy (15 mg/day) followed by thyroid hormone was begun, which dramatically improved her symptoms and abnormalities in laboratory tests. Within two weeks, she was able to walk more than 500 m. Flexion
123
M. Ikeuchi et al. Fig. 1 The patient at the time of admission to the hospital. Note the flexed position of the hips and knees
Table 1 Range of motion in each joint Hip
Knee
Ankle
Ext
Flex
Abd
Add
Int rot
Ext rot
Ext
Flex
Dorsiflex
Plantar flex
R
-30
125
20
0
0
30
-45
120
10
30
L
-30
110
20
0
0
30
-40
120
10
30
contractures of her legs completely resolved within three months after the start of replacement therapy (Fig. 4). In addition, she felt less tired than before and gained 5 kg in weight. She has been receiving cortisol and thyroid hormone treatment for the last six years, and in that time the flexion contractures have never recurred. At her last visit, her body height and weight were 152 cm and 58 kg, respectively.
Discussion Sheehan, in 1938, described the occurrence of pituitary infarction and panhypopituitarism following obstetric hemorrhage. Sheehan estimated the prevalence of the syndrome as 100–200 per 1,000,000 women approximately 50 years ago [1]. Because of advances in obstetric care, the frequency of SS has since greatly decreased, and SS has become a forgotten disorder in Western populations. The pattern of hormone deficiencies in SS is variable. The main
123
involvement is the secretion of GH and prolactin (88–100 %), while deficiencies in ACTH, gonadotropins, and TSH range from 42 to 76 % [3]. The resulting symptoms depend on the pituitary hormones affected and secondary deficiencies of the target organ hormones, including adrenal insufficiency and hypothyroidism. It is reported that the initial manifestation of SS is generally lactation failure, followed by failure to resume menses, and genital hair loss. Musculoskeletal abnormalities are uncommon manifestations of this disease, especially flexion contractures of the legs. In our case, the typical initial manifestation of SS was masked by a previous breastfeeding problem, total hysterectomy, and naturally sparse genital hair. Consequently, flexion contracture was the only complaint. It is likely that adrenal insufficiency secondary to SS caused the flexion contractures of the legs, because there are several reports describing this very rare complication in patients with adrenal insufficiency [4]. Patients with chronic adrenal insufficiency usually present with
Contractures in endocrine disease Fig. 2 Radiographs of the patient’s hip (a) and knee joints (b) taken upon admission to the hospital
weakness, hypotension, weight loss, anorexia, nausea and vomiting, pale skin without marked anemia, amenorrhea, and hypoglycemia [5]. In our case, although she felt less tired and gained weight after the start of cortisol replacement therapy, neither general fatigue nor weight loss were her complaints. The pathophysiology of flexion contractures is largely unknown, although Odagaki et al. [5] suggested that glucocorticoids are necessary to maintain some metabolic functions of the muscle in addition to energy metabolism and immunosuppressive effects. Jakobi et al. [6] suggested that the contractile properties of
muscles are dependent on glucocorticoid. Furthermore, it is reported that neither isolated hyponatremia nor hypoadrenalism cause muscle cramps and contractures [7, 8]. Therefore, it is possible that the coexistence of hyponatremia and low cortisol levels might be necessary in the genesis of flexion contractures. The clinical picture of this patient resembled stiff-man syndrome. Stiff-man syndrome is a rare neurologic syndrome characterized by similar muscle spasticity [9]. In stiff-man syndrome, agonist and antagonist muscles are affected equally. Therefore, the patient becomes rigid in
123
M. Ikeuchi et al. Table 2 Results of a laboratory examination performed at the time of hospital admission
WBC
5600/ll
Na
143 mEq/l
RBC
336 9 104/ll ;
K
3.8 mEq/l
Hb
9.6 g/dl ;
Cl
104 mEq/l
Ht Plt
27.3 % ; 18.5 9 104/ll
Ca P
8.3 mEq/l 3.0 mEq/l
TP
8.0 g/dl
CPK
898 U/l :
Alb
4.2 g/dl
T-Cho
257 mg/dl :
GPT
27 IU/l
Cr
0.5 mg/dl
GOT
59 IU/l :
BUN
9 mg/dl
LDH
339 IU/l :
ALP
241 IU/l
CRP
0.4 mg/dl
cGTP
26 IU/l
RF
3.6 IU/ml
ChE
253 IU/l
ANF
–
ACTH
11 pg/ml ;
Cortisol
1.06 lg/dl ;
GH
0.06 ng/ml ;
TSH
2.98 lIU/ml
Free T3
1.14 lg/ml ;
PRL
1.6 ng/ml ;
Free T4
0.18 ng/dl ;
LH
1.8 mIU/ml ;
FSH
8.0 mIU/ml ;
E2
\10 pg/ml ;
Fig. 3 Sagittal (a) and coronal (b) T1-weighted images. Arrows indicate the atrophic pituitary gland (empty sella)
extension, and limbs are not fixed in flexion. The EMG in stiff-man syndrome shows continuous motor unit activity with a positive response to diazepam, while flexion contractures are characterized by variable EMG. In our case, EMG in the legs showed no abnormalities. It is suggested that the changes in the EMG in flexion contractures seem to depend partly on the duration and severity of adrenal insufficiency. Most patients with joint pain are referred to an orthopedic clinic. Orthopedic surgeons are familiar with joint pain and flexion contractures of the legs, which are often associated with common joint diseases such as osteoarthritis
123
and inflammatory arthritis. However, such symptoms could occur in patients with endocrine abnormalities. As seen in the present case, endocrinological examination is critical to attaining the correct diagnosis. Furthermore, a detailed interview regarding the delivery aids the process of diagnosing SS. If there is no evidence suggesting common orthopedic diseases such as osteoarthritis, rheumatic diseases, and neuromuscular diseases, endocrine diseases should be taken into account. Specifically, a serum electrolyte test should be performed initially. If the serum sodium level is less than normal, adrenal insufficiency should be suspected.
Contractures in endocrine disease Fig. 4 The patient after three months of treatment
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Sheehan HL. The frequency of post-partum hypopituitarism. J Obstet Gynaecol Br Commonw. 1965;72:103–11. 2. Kelestimur F. Sheehan’s syndrome. Pituitary. 2003;6(4):181–8. 3. Sert M, Tetiker T, Kirim S, Kocak M. Clinical report of 28 patients with Sheehan’s syndrome. Endocr J. 2003;50(3):297–301. 4. Nishikawa T. Flexion contractures possibly reflect the existence of hypocortisolism. Intern Med. 2003;42(8):629–31.
5. Odagaki T, Noguchi Y, Fukui T. Flexion contractures of the legs as the initial manifestation of adrenocortical insufficiency. Intern Med. 2003;42(8):710–3. 6. Jakobi JM, Killinger DW, Wolfe BM, Mahon JL, Rice CL. Quadriceps muscle function and fatigue in women with Addison’s disease. Muscle Nerve. 2001;24(8):1040–9. 7. McGee SR. Muscle cramps. Arch Intern Med. 1990;150(3):511–8. 8. Ebinger G, Six R, Bruyland M, Somers G. Flexion contractures: a forgotten symptom in Addison’s disease and hypopituitarism. Lancet. 1986;2(8511):858. 9. George TM, Burke JM, Sobotka PA, Greenberg HS, Vinik AI. Resolution of stiff-man syndrome with cortisol replacement in a patient with deficiencies of ACTH, growth hormone, and prolactin. N Engl J Med. 1984;310(23):1511–3.
123
CASE REPORT
Flexion contractures of the legs as the manifestation of secondary adrenal insufficiency due to Sheehan’s syndrome Masahiko Ikeuchi • Masashi Izumi • Tatsunori Ikemoto • Toshikazu Tani
Received: 7 May 2012 / Accepted: 24 August 2012 Ó The Japanese Orthopaedic Association 2012
Introduction Sheehan’s syndrome (SS) is postpartum hypopituitarism caused by necrosis of the pituitary gland following severe obstetric hemorrhage [1]. Advances in obstetric care have greatly reduced the frequency of SS, particularly in developed countries. The syndrome generally initially manifests as lactation failure, followed by failure to resume menses, and genital hair loss [2]. Herein, we report a rare case of SS presenting with flexion contractures of the legs 20 years after delivery. Consent for the publication of this case was obtained from the patient.
Case report A 53-year-old woman presented with flexion contractures of the legs (Fig. 1). She was unable to walk and used a wheelchair. Two years prior to her visit to our clinic, she felt pain and stiffness in her knees and hips. After a while she noticed that she was unable to fully extend her knees and hips, and then flexion contractures of her legs gradually developed. On admission, she was alert and oriented. Painful flexion contractures were observed in the hips and knees (Table 1). Nevertheless, radiographs showed no obvious abnormalities except for the flexed positions of the hips and knees (Fig. 2). No major joint problem with her upper extremities was observed. Her body height and weight
M. Ikeuchi (&) M. Izumi T. Ikemoto T. Tani Department of Orthopaedic Surgery, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan e-mail: [email protected]
were 141 cm and 52 kg, respectively. The physical findings for her neck, chest, and abdomen were unremarkable. No neurological abnormalities were detected. Laboratory examination showed normocytic anemia, mild elevation of serum GOT, LDH, CPK, and T-Cho (Table 2). No particular isozyme pattern of CPK and LDH was noted. The results of a nerve conduction study and electromyography (EMG) were unremarkable. Muscle biopsy of the rectus femoris showed no specific findings suggesting myopathies. Autoimmune serological markers associated with rheumatic diseases were negative. Although the serum sodium was normal on admission, repeated laboratory examination showed a remarkable decrease in serum sodium from 136 to 113 mmol/l within two weeks. Her fasting plasma glucose was normal. After consultation with a physician, an endocrinological examination was performed. The results revealed that she had panhypopituitarism (Table 2). Anti-pituitary antibody was negative. MRI of her brain showed atrophy of her pituitary gland with a completely empty sella (Fig. 3). A later interview revealed that she suffered severe hemorrhage (approximately 3000 ml of blood lost) at her fourth delivery, resulting in severe shock when she was 33 year old, and total hysterectomy was carried out. She had already experienced breastfeeding problems and changed it to formula feeding with the third child. Therefore, she did not complain of lactation failure after her fourth delivery. Based on her past history, laboratory findings for her pituitary function, and a lack of specific findings on radiographs, EMG, and muscle biopsy, a diagnosis of panhypopituitarism caused by SS was made. Cortisol replacement therapy (15 mg/day) followed by thyroid hormone was begun, which dramatically improved her symptoms and abnormalities in laboratory tests. Within two weeks, she was able to walk more than 500 m. Flexion
123
M. Ikeuchi et al. Fig. 1 The patient at the time of admission to the hospital. Note the flexed position of the hips and knees
Table 1 Range of motion in each joint Hip
Knee
Ankle
Ext
Flex
Abd
Add
Int rot
Ext rot
Ext
Flex
Dorsiflex
Plantar flex
R
-30
125
20
0
0
30
-45
120
10
30
L
-30
110
20
0
0
30
-40
120
10
30
contractures of her legs completely resolved within three months after the start of replacement therapy (Fig. 4). In addition, she felt less tired than before and gained 5 kg in weight. She has been receiving cortisol and thyroid hormone treatment for the last six years, and in that time the flexion contractures have never recurred. At her last visit, her body height and weight were 152 cm and 58 kg, respectively.
Discussion Sheehan, in 1938, described the occurrence of pituitary infarction and panhypopituitarism following obstetric hemorrhage. Sheehan estimated the prevalence of the syndrome as 100–200 per 1,000,000 women approximately 50 years ago [1]. Because of advances in obstetric care, the frequency of SS has since greatly decreased, and SS has become a forgotten disorder in Western populations. The pattern of hormone deficiencies in SS is variable. The main
123
involvement is the secretion of GH and prolactin (88–100 %), while deficiencies in ACTH, gonadotropins, and TSH range from 42 to 76 % [3]. The resulting symptoms depend on the pituitary hormones affected and secondary deficiencies of the target organ hormones, including adrenal insufficiency and hypothyroidism. It is reported that the initial manifestation of SS is generally lactation failure, followed by failure to resume menses, and genital hair loss. Musculoskeletal abnormalities are uncommon manifestations of this disease, especially flexion contractures of the legs. In our case, the typical initial manifestation of SS was masked by a previous breastfeeding problem, total hysterectomy, and naturally sparse genital hair. Consequently, flexion contracture was the only complaint. It is likely that adrenal insufficiency secondary to SS caused the flexion contractures of the legs, because there are several reports describing this very rare complication in patients with adrenal insufficiency [4]. Patients with chronic adrenal insufficiency usually present with
Contractures in endocrine disease Fig. 2 Radiographs of the patient’s hip (a) and knee joints (b) taken upon admission to the hospital
weakness, hypotension, weight loss, anorexia, nausea and vomiting, pale skin without marked anemia, amenorrhea, and hypoglycemia [5]. In our case, although she felt less tired and gained weight after the start of cortisol replacement therapy, neither general fatigue nor weight loss were her complaints. The pathophysiology of flexion contractures is largely unknown, although Odagaki et al. [5] suggested that glucocorticoids are necessary to maintain some metabolic functions of the muscle in addition to energy metabolism and immunosuppressive effects. Jakobi et al. [6] suggested that the contractile properties of
muscles are dependent on glucocorticoid. Furthermore, it is reported that neither isolated hyponatremia nor hypoadrenalism cause muscle cramps and contractures [7, 8]. Therefore, it is possible that the coexistence of hyponatremia and low cortisol levels might be necessary in the genesis of flexion contractures. The clinical picture of this patient resembled stiff-man syndrome. Stiff-man syndrome is a rare neurologic syndrome characterized by similar muscle spasticity [9]. In stiff-man syndrome, agonist and antagonist muscles are affected equally. Therefore, the patient becomes rigid in
123
M. Ikeuchi et al. Table 2 Results of a laboratory examination performed at the time of hospital admission
WBC
5600/ll
Na
143 mEq/l
RBC
336 9 104/ll ;
K
3.8 mEq/l
Hb
9.6 g/dl ;
Cl
104 mEq/l
Ht Plt
27.3 % ; 18.5 9 104/ll
Ca P
8.3 mEq/l 3.0 mEq/l
TP
8.0 g/dl
CPK
898 U/l :
Alb
4.2 g/dl
T-Cho
257 mg/dl :
GPT
27 IU/l
Cr
0.5 mg/dl
GOT
59 IU/l :
BUN
9 mg/dl
LDH
339 IU/l :
ALP
241 IU/l
CRP
0.4 mg/dl
cGTP
26 IU/l
RF
3.6 IU/ml
ChE
253 IU/l
ANF
–
ACTH
11 pg/ml ;
Cortisol
1.06 lg/dl ;
GH
0.06 ng/ml ;
TSH
2.98 lIU/ml
Free T3
1.14 lg/ml ;
PRL
1.6 ng/ml ;
Free T4
0.18 ng/dl ;
LH
1.8 mIU/ml ;
FSH
8.0 mIU/ml ;
E2
\10 pg/ml ;
Fig. 3 Sagittal (a) and coronal (b) T1-weighted images. Arrows indicate the atrophic pituitary gland (empty sella)
extension, and limbs are not fixed in flexion. The EMG in stiff-man syndrome shows continuous motor unit activity with a positive response to diazepam, while flexion contractures are characterized by variable EMG. In our case, EMG in the legs showed no abnormalities. It is suggested that the changes in the EMG in flexion contractures seem to depend partly on the duration and severity of adrenal insufficiency. Most patients with joint pain are referred to an orthopedic clinic. Orthopedic surgeons are familiar with joint pain and flexion contractures of the legs, which are often associated with common joint diseases such as osteoarthritis
123
and inflammatory arthritis. However, such symptoms could occur in patients with endocrine abnormalities. As seen in the present case, endocrinological examination is critical to attaining the correct diagnosis. Furthermore, a detailed interview regarding the delivery aids the process of diagnosing SS. If there is no evidence suggesting common orthopedic diseases such as osteoarthritis, rheumatic diseases, and neuromuscular diseases, endocrine diseases should be taken into account. Specifically, a serum electrolyte test should be performed initially. If the serum sodium level is less than normal, adrenal insufficiency should be suspected.
Contractures in endocrine disease Fig. 4 The patient after three months of treatment
Conflict of interest of interest.
The authors declare that they have no conflict
References 1. Sheehan HL. The frequency of post-partum hypopituitarism. J Obstet Gynaecol Br Commonw. 1965;72:103–11. 2. Kelestimur F. Sheehan’s syndrome. Pituitary. 2003;6(4):181–8. 3. Sert M, Tetiker T, Kirim S, Kocak M. Clinical report of 28 patients with Sheehan’s syndrome. Endocr J. 2003;50(3):297–301. 4. Nishikawa T. Flexion contractures possibly reflect the existence of hypocortisolism. Intern Med. 2003;42(8):629–31.
5. Odagaki T, Noguchi Y, Fukui T. Flexion contractures of the legs as the initial manifestation of adrenocortical insufficiency. Intern Med. 2003;42(8):710–3. 6. Jakobi JM, Killinger DW, Wolfe BM, Mahon JL, Rice CL. Quadriceps muscle function and fatigue in women with Addison’s disease. Muscle Nerve. 2001;24(8):1040–9. 7. McGee SR. Muscle cramps. Arch Intern Med. 1990;150(3):511–8. 8. Ebinger G, Six R, Bruyland M, Somers G. Flexion contractures: a forgotten symptom in Addison’s disease and hypopituitarism. Lancet. 1986;2(8511):858. 9. George TM, Burke JM, Sobotka PA, Greenberg HS, Vinik AI. Resolution of stiff-man syndrome with cortisol replacement in a patient with deficiencies of ACTH, growth hormone, and prolactin. N Engl J Med. 1984;310(23):1511–3.
123