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‘Dementia with contractures’ as presenting signs of secondary adrenocortical insufficiency
‘Dementia with contractures’ as presenting signs of secondary adrenocortical insuffkiency. J.J. van der Sande*,
A.P. van Seters* *, and A.R. Wintzen*
Introduction Summary
Dementia is usually caused by irreversible cerebral degeneration. However, in every patient with diffuse deterioration of the mental functions, treatable underlying disorders should be exluded. We present a patient with a very unusual clinical picture and a rare causal disorder. Case report In March 1976, a 61-year-old former agricultural labourer was admitted with an eighteen month history of a variety of symptoms. In October 1974 the patient had started to complain of general fatigue and pain in his thighs. Two months later he gradually developed impairment of memory, loss of interest, apathy, and disorientation. Both legs showed a tendency to painful flexion in the hips and knees, which interfered with walking. No general medical, neurological, orthopedic or rheumatological causes could be identified, and spontaneous improvement permitted the patient more or less to resume his daily physical activities at home. During the following year his leg symptoms fluctuated, but mentally there was no improvement. In February 1976 further deterioration led to great difficulty in walking, increasing confusion, restlessness at night, and urinary incontinence. Physical examination on admission revealed a
* Departments of Neurology’
and Endocrinology*
Report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed.
Key words: dementia, pituitary adenoma
pale-faced apathetic man who was bedridden, disorientated in time, and subject to fluctuating drowsiness. Blood pressure was 130/80 mmHg, heart rate regular 68/min., body weight 88 kg, apparent height 172 cm (182 cm prior to illness), congenital club feet, and ankle edema. Except for characteristic horizontal wrinkles at the corners of his mouth, signs of pituitary failure were lacking. Neurological examination revealed dysarthria, dysstasia, and a gait disorder with dragging of the feet. Hips and knees were constantly held in flexion which made standing in an upright position and walking hardly possible (Fig. 1). Severe rigidity of the legs interfered with active
*, Leiden University Medical Center, The Netherlands.
Address for correspondence and reprint requests: J.J. van der Sande, Department of Neurology, Municipal Hospital Slotervaart, Amsterdam, The Netherlands. Accepted 24.9.85 Clin Neurol Neurosurg 1986. Vol. 88-1
53
___II-_ Fig. 1. The patient
A before
(A) and after (B) treatment.
and passive movements. The intense rigidity of the abdominal muscles rendered palpation of the abdomen virtually impossible. In contrast, muscle tone in the arms was normal. No Parkinsonian features and no paresis were found. Ankle jerks were absent, plantar responses were equivocal. Palmomental and snout reflexes could be elicited. - Radiological examination of the skull suggested a minimal asymmetry of the floor of the sella turcica, but tomography of the sella was normal. - EEG revealed diffuse slowing in theta and delta frequencies without focal abnormalities. - CSF was clear and colourless, under a pressure of 12 cm H,O, with an elevated protein content of 1.16 g/l, normal cell count, and no abnormal cells. - Laboratory investigations showed an ESR of 34 mm (first hour), Hb concentration of 7.4 mmoY1 (12.0 g/dl) with normal cell indices, WBC of 4.9 x 10y/l. Measurement of plasma electrolytes, blood urea nitrogen, creatinine, creatine phosphokinase, cholesterol, SLDH, 54
serum glucose, calcium and phosphate, plasma bilirubin, alkaline phosphatase, vitamin B 12 and folate were all normal. Plasma cortisol concentrations at 8 a.m. varied from 0.09 to 0.18 pmoUl (3.3 - 6.5 &dl; normal range 0.16 - 0.50 pmol/l) and excretion of 17-oxogenic steroids was 8.1 - 18.3 pmol/24 h (2.3 - 5.3 mg; normal range 14 - 90 pmoU24 h). After ACTH infusion (400 pg ACTH’-24 for 4 h) cortisol rose to 0.55 pmol/l, which indicated secondary adrenocortical insufficiency. Plasma testosterone concentration was 1.5 nmol/l (43 ng/dl; normal range 13.9 - 52.2 nmoV1). which could also be explained by hypopituitarism. Thyroid function was slightly decreased: PBI 0.23 - 0.28 pmol/l (normal 0.32 - 0.63). T4 78.7 nmol/l (6.1 pg/dl, normal 70 - 160 nmoV1) and free thyroxin index 14.9 (normal 15.4 - 52.8). Basal TSH release was slightly elevated (12 mu/I, normal < 9 mu/l) and responsive to TSHreleasing hormone, (20 minutes > 40, 60 minutes > 40 mu/I, following 200 pg TRH intravenously), as can be found in hypothalamic disre-
gulation’. Basal prolactin was within normal limits. No circulating antibodies to adrenal cortex, thyroid colloid and cytoplasm, striated or smooth muscle were demonstrated. Rose test was normal. Biopsy of muscle, skin, fascia, and temporal artery showed no significant changes. During hospitalization some of the clinical features appeared to fluctuate spontaneously as had previously been the case. Within three weeks consciousness became clear and orientation intact, but the patient remained apathetic and forgetful. Neuropsychological assessment at that stage confirmed impairment of immediate recall, short and long term memory, compatible with diffuse mental deterioration accompanied by severe visual-constructive apraxia. Walking without support became possible, but was still severely hampered by the painful rigidity of the legs. It was decided to start treatment with slowly increasing doses of thyroid powder (thyranonR, up to 50 mg. daily) and physiotherapy, but no effect was observed during the following 5 weeks. However, administration of hydrocortisone 30 mg daily was followed within 24 hours by a striking and lasting clinical improvement, with decrease and eventually disappearance of pain and rigidity, increase of mobility of the joints, and gradual mental improvement. During the following months the patient’s clinical, neurological and psychological condition returned to normal. Radiological evidence of a pituitary tumour was eventually provided in 1979, and a suprasellar expansion was demonstrated by CT-scan in 1980: tumour classification IIIb according to Hardy2. EEG, repeated in 1980, was normal. Neuropsychological assessment in 1980 showed a striking improvement compared with the previous examination in 1976: MQ on the Wechsler Memory Scale had increased from 96 to 116, with a remarkable improvement in immediate recall, short and long term memory and visual-constructive performance. Visual fields remained unrestricted. Serum prolactin remained normal (6.6 ug/l). There was a decrease in response of LH and FSH to gonadotrophin-releasing hormone. This nonfunctioning pituitary tumour responded to bromocriptine, which was started in March 1981, with considerable shrinkage (tumour classifica-
tion IIP’). Neurological symptoms and signs did not recur, and at present, after a follow-up of 9 years, the patient is functioning normally without physiotherapy. The present medication is hydrocortisone 30 mg daily, thyranonR 75 mg daily and bromocriptine 7.5 mg daily. Discussion
In this patient the response to hydrocortisone treatment and the clinical course during the following years confirmed adrenocortical insufficiency secondary to a non-functioning pituitary chromophobe adenoma. The absence of the ordinary clinical features of adrenocortical insufficiency such as hypotension or anorexia, was striking. The response to bromocriptine ruled out the presence of craniopharyngioma or other (supra)sellar tumours. Neuropsychiatric disturbances in patients with adrenocortical insufficiency may range from nervousness, irritability and depression to marked personality changes, disorientation, memory disturbances, alteration of consciousness, psychosis, and delirium3. Painful flexion contractures of the legs and the abdominal muscles are very rare but characteristic sequelae of primary3,4 and secondary 5,6 adrenocortical insufficiency. Their typical distribution and properties could have been considered as another argument against hypothyroidism being an important factor, although general muscle pain and difficulty to relax after muscular contraction are known to occur as complications of the latter disorder. The underlying mechanism of flexion contractures in adrenocortical insufficiency is still unexplained. It should be pointed out that the term ‘contracture’ is generally reserved for a permanent deformity usually attributed to fibrosis. ‘Rigidity’ might consequently be the more appropriate term in such cases. Electromyogram and microscopic examination of muscle, nerve and tendons have been reported normaP. Thorn’ has suggested that the contractures are not of muscular origin, but are due to an excessive accumulation of sodium and a decrease of potassium in the tendons, though no conclusive evidence for this hypothesis has been provided. Furthermore, Devos et al.8 observed that contractures could occur independently of the serum concentrations of sodium and potassium, 55
and may even develop during treatment of hyponatremia in Addison’s disease. The contractures should be differentiated from the so-called stiff-man syndrome, which was once reported as a complication of adrenocortical insufficiencyh. The latter syndrome usually involves both upper and lower limbs, and is characterized by paroxysms of intense muscle spasms after sudden stimuli including noises and emotions. Finally, care should be taken that the combination of flexion contractures with mental deterioration does not lead to an erroneous diagnosis of irreversible degenerative disease of the central nervous system, in which case an excellent opportunity for successful treatment would be missed. Acknowledgements Critical comments were given by Mr. M.W. Miss M. van den Elzen typed the manuscript.
Fidler FRCS.
References ~NGBARSH, WOEBER KA. The thyroid gland. In Williams RH ed. Textbook of Endocrinology. Philadelphia. Saunders, 1981:164. HARDY J. Transsphenoidal surgery of hypersecrefing pituitary tumors. In Kohler PO. Ross CT (eds): Diagnosis and treatment of pituitary tumors. Amsterdam - New York; Excerpta Medica Amsterdam/Amsterdam Elscvier Publishing Co, 1973: 179-94. VAN DER SANDEJJ.VAN S~TERS AP. The adrenal gland: its relationship to neurology. In Vinken PJ, Bruyn GW: Handbook of Clinical neurology. Amsterdam: NorthHolland Publishing Company, 19X0: 39:469-515. BERGOUIONAN M. Nouvelle observation de contracture abdomino-crurale en ilcxion au tours de la maladie d’Addison. Rev Neurol 1962; 104:329-32. SLATER JDH. Stiff-man syndrome with Atypical Hypopituitarism. Proc Royal Sot Med 1960; 53:X67-9. ADAMS RD. Diseases of Muscle, a Study of Pathology. 3rd Ed. Maryland-New York-Evanston-San Francisco-London: Hagerstown. 1975:486-7. IHORN GW. The Diagnosis and Treatment of Adrenal Insufficiency. Springfield. Ill. Thomas. 1951. o~vos PH. oss~& A.. FOIJRNIER I), WAROT P. Traitement de I’encephalopathie addisonienne. Apparition d’unc conctracture abdomino-crurale. La Presse Medicalc 1984: 13:946. GEORGtTM.BURKEJM,SOBOTKA
PA,GREENBERG
HS.VINlK
Resolution of Stiff-man syndrome with cortisol replacement in a patient with deficiencies of ACTH, growth hormone,andprolactin.NEnglJMed1984;310:1511-3. AJ.
A.P. van Seters* *, and A.R. Wintzen*
Introduction Summary
Dementia is usually caused by irreversible cerebral degeneration. However, in every patient with diffuse deterioration of the mental functions, treatable underlying disorders should be exluded. We present a patient with a very unusual clinical picture and a rare causal disorder. Case report In March 1976, a 61-year-old former agricultural labourer was admitted with an eighteen month history of a variety of symptoms. In October 1974 the patient had started to complain of general fatigue and pain in his thighs. Two months later he gradually developed impairment of memory, loss of interest, apathy, and disorientation. Both legs showed a tendency to painful flexion in the hips and knees, which interfered with walking. No general medical, neurological, orthopedic or rheumatological causes could be identified, and spontaneous improvement permitted the patient more or less to resume his daily physical activities at home. During the following year his leg symptoms fluctuated, but mentally there was no improvement. In February 1976 further deterioration led to great difficulty in walking, increasing confusion, restlessness at night, and urinary incontinence. Physical examination on admission revealed a
* Departments of Neurology’
and Endocrinology*
Report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed.
Key words: dementia, pituitary adenoma
pale-faced apathetic man who was bedridden, disorientated in time, and subject to fluctuating drowsiness. Blood pressure was 130/80 mmHg, heart rate regular 68/min., body weight 88 kg, apparent height 172 cm (182 cm prior to illness), congenital club feet, and ankle edema. Except for characteristic horizontal wrinkles at the corners of his mouth, signs of pituitary failure were lacking. Neurological examination revealed dysarthria, dysstasia, and a gait disorder with dragging of the feet. Hips and knees were constantly held in flexion which made standing in an upright position and walking hardly possible (Fig. 1). Severe rigidity of the legs interfered with active
*, Leiden University Medical Center, The Netherlands.
Address for correspondence and reprint requests: J.J. van der Sande, Department of Neurology, Municipal Hospital Slotervaart, Amsterdam, The Netherlands. Accepted 24.9.85 Clin Neurol Neurosurg 1986. Vol. 88-1
53
___II-_ Fig. 1. The patient
A before
(A) and after (B) treatment.
and passive movements. The intense rigidity of the abdominal muscles rendered palpation of the abdomen virtually impossible. In contrast, muscle tone in the arms was normal. No Parkinsonian features and no paresis were found. Ankle jerks were absent, plantar responses were equivocal. Palmomental and snout reflexes could be elicited. - Radiological examination of the skull suggested a minimal asymmetry of the floor of the sella turcica, but tomography of the sella was normal. - EEG revealed diffuse slowing in theta and delta frequencies without focal abnormalities. - CSF was clear and colourless, under a pressure of 12 cm H,O, with an elevated protein content of 1.16 g/l, normal cell count, and no abnormal cells. - Laboratory investigations showed an ESR of 34 mm (first hour), Hb concentration of 7.4 mmoY1 (12.0 g/dl) with normal cell indices, WBC of 4.9 x 10y/l. Measurement of plasma electrolytes, blood urea nitrogen, creatinine, creatine phosphokinase, cholesterol, SLDH, 54
serum glucose, calcium and phosphate, plasma bilirubin, alkaline phosphatase, vitamin B 12 and folate were all normal. Plasma cortisol concentrations at 8 a.m. varied from 0.09 to 0.18 pmoUl (3.3 - 6.5 &dl; normal range 0.16 - 0.50 pmol/l) and excretion of 17-oxogenic steroids was 8.1 - 18.3 pmol/24 h (2.3 - 5.3 mg; normal range 14 - 90 pmoU24 h). After ACTH infusion (400 pg ACTH’-24 for 4 h) cortisol rose to 0.55 pmol/l, which indicated secondary adrenocortical insufficiency. Plasma testosterone concentration was 1.5 nmol/l (43 ng/dl; normal range 13.9 - 52.2 nmoV1). which could also be explained by hypopituitarism. Thyroid function was slightly decreased: PBI 0.23 - 0.28 pmol/l (normal 0.32 - 0.63). T4 78.7 nmol/l (6.1 pg/dl, normal 70 - 160 nmoV1) and free thyroxin index 14.9 (normal 15.4 - 52.8). Basal TSH release was slightly elevated (12 mu/I, normal < 9 mu/l) and responsive to TSHreleasing hormone, (20 minutes > 40, 60 minutes > 40 mu/I, following 200 pg TRH intravenously), as can be found in hypothalamic disre-
gulation’. Basal prolactin was within normal limits. No circulating antibodies to adrenal cortex, thyroid colloid and cytoplasm, striated or smooth muscle were demonstrated. Rose test was normal. Biopsy of muscle, skin, fascia, and temporal artery showed no significant changes. During hospitalization some of the clinical features appeared to fluctuate spontaneously as had previously been the case. Within three weeks consciousness became clear and orientation intact, but the patient remained apathetic and forgetful. Neuropsychological assessment at that stage confirmed impairment of immediate recall, short and long term memory, compatible with diffuse mental deterioration accompanied by severe visual-constructive apraxia. Walking without support became possible, but was still severely hampered by the painful rigidity of the legs. It was decided to start treatment with slowly increasing doses of thyroid powder (thyranonR, up to 50 mg. daily) and physiotherapy, but no effect was observed during the following 5 weeks. However, administration of hydrocortisone 30 mg daily was followed within 24 hours by a striking and lasting clinical improvement, with decrease and eventually disappearance of pain and rigidity, increase of mobility of the joints, and gradual mental improvement. During the following months the patient’s clinical, neurological and psychological condition returned to normal. Radiological evidence of a pituitary tumour was eventually provided in 1979, and a suprasellar expansion was demonstrated by CT-scan in 1980: tumour classification IIIb according to Hardy2. EEG, repeated in 1980, was normal. Neuropsychological assessment in 1980 showed a striking improvement compared with the previous examination in 1976: MQ on the Wechsler Memory Scale had increased from 96 to 116, with a remarkable improvement in immediate recall, short and long term memory and visual-constructive performance. Visual fields remained unrestricted. Serum prolactin remained normal (6.6 ug/l). There was a decrease in response of LH and FSH to gonadotrophin-releasing hormone. This nonfunctioning pituitary tumour responded to bromocriptine, which was started in March 1981, with considerable shrinkage (tumour classifica-
tion IIP’). Neurological symptoms and signs did not recur, and at present, after a follow-up of 9 years, the patient is functioning normally without physiotherapy. The present medication is hydrocortisone 30 mg daily, thyranonR 75 mg daily and bromocriptine 7.5 mg daily. Discussion
In this patient the response to hydrocortisone treatment and the clinical course during the following years confirmed adrenocortical insufficiency secondary to a non-functioning pituitary chromophobe adenoma. The absence of the ordinary clinical features of adrenocortical insufficiency such as hypotension or anorexia, was striking. The response to bromocriptine ruled out the presence of craniopharyngioma or other (supra)sellar tumours. Neuropsychiatric disturbances in patients with adrenocortical insufficiency may range from nervousness, irritability and depression to marked personality changes, disorientation, memory disturbances, alteration of consciousness, psychosis, and delirium3. Painful flexion contractures of the legs and the abdominal muscles are very rare but characteristic sequelae of primary3,4 and secondary 5,6 adrenocortical insufficiency. Their typical distribution and properties could have been considered as another argument against hypothyroidism being an important factor, although general muscle pain and difficulty to relax after muscular contraction are known to occur as complications of the latter disorder. The underlying mechanism of flexion contractures in adrenocortical insufficiency is still unexplained. It should be pointed out that the term ‘contracture’ is generally reserved for a permanent deformity usually attributed to fibrosis. ‘Rigidity’ might consequently be the more appropriate term in such cases. Electromyogram and microscopic examination of muscle, nerve and tendons have been reported normaP. Thorn’ has suggested that the contractures are not of muscular origin, but are due to an excessive accumulation of sodium and a decrease of potassium in the tendons, though no conclusive evidence for this hypothesis has been provided. Furthermore, Devos et al.8 observed that contractures could occur independently of the serum concentrations of sodium and potassium, 55
and may even develop during treatment of hyponatremia in Addison’s disease. The contractures should be differentiated from the so-called stiff-man syndrome, which was once reported as a complication of adrenocortical insufficiencyh. The latter syndrome usually involves both upper and lower limbs, and is characterized by paroxysms of intense muscle spasms after sudden stimuli including noises and emotions. Finally, care should be taken that the combination of flexion contractures with mental deterioration does not lead to an erroneous diagnosis of irreversible degenerative disease of the central nervous system, in which case an excellent opportunity for successful treatment would be missed. Acknowledgements Critical comments were given by Mr. M.W. Miss M. van den Elzen typed the manuscript.
Fidler FRCS.
References ~NGBARSH, WOEBER KA. The thyroid gland. In Williams RH ed. Textbook of Endocrinology. Philadelphia. Saunders, 1981:164. HARDY J. Transsphenoidal surgery of hypersecrefing pituitary tumors. In Kohler PO. Ross CT (eds): Diagnosis and treatment of pituitary tumors. Amsterdam - New York; Excerpta Medica Amsterdam/Amsterdam Elscvier Publishing Co, 1973: 179-94. VAN DER SANDEJJ.VAN S~TERS AP. The adrenal gland: its relationship to neurology. In Vinken PJ, Bruyn GW: Handbook of Clinical neurology. Amsterdam: NorthHolland Publishing Company, 19X0: 39:469-515. BERGOUIONAN M. Nouvelle observation de contracture abdomino-crurale en ilcxion au tours de la maladie d’Addison. Rev Neurol 1962; 104:329-32. SLATER JDH. Stiff-man syndrome with Atypical Hypopituitarism. Proc Royal Sot Med 1960; 53:X67-9. ADAMS RD. Diseases of Muscle, a Study of Pathology. 3rd Ed. Maryland-New York-Evanston-San Francisco-London: Hagerstown. 1975:486-7. IHORN GW. The Diagnosis and Treatment of Adrenal Insufficiency. Springfield. Ill. Thomas. 1951. o~vos PH. oss~& A.. FOIJRNIER I), WAROT P. Traitement de I’encephalopathie addisonienne. Apparition d’unc conctracture abdomino-crurale. La Presse Medicalc 1984: 13:946. GEORGtTM.BURKEJM,SOBOTKA
PA,GREENBERG
HS.VINlK
Resolution of Stiff-man syndrome with cortisol replacement in a patient with deficiencies of ACTH, growth hormone,andprolactin.NEnglJMed1984;310:1511-3. AJ.