C Hobson, H Foyaca-Sibat, L Ibanez-Valdes, B Hobson
epilepsy, hypogonadotropic hypogonadism, pituitary dysfunction, systemic lupus erythematosus
C Hobson, H Foyaca-Sibat, L Ibanez-Valdes, B Hobson. Epilepsy, Hypogonadotropic Hypogonadism, and Systemic Lupus Erythematosus. The Internet Journal of Neurology. 2006 Volume 6 Number 1.
We report on a patient with uncontrolled epilepsy, hypogonadotropic hypogonadism and systemic lupus erythematosus in a rural setting of the Eastern Cape, South Africa.
Gonadal function is significantly affected in many acute and chronic systemic diseases. As the function of the testes and the ovaries is determined by the integrity of the hypothalamic–pituitary–gonadal axis, it is obvious that a systemic disease may affect one or more levels of the axis in such a manner that the gonadal dysfunction may have various clinical and laboratory manifestations. In this brief review, the most common disturbances seen in the main systemic diseases will be discussed, and the relationship between epilepsy, hypogonadotropic hypogonadism and systemic lupus erythematosus examined.
A 23 year old male presented at Nelson Mandela Academic Hospital (Mthatha) with a longstanding history of uncontrolled epilepsy. He experienced up to 2 fits per day, which were generalised tonic-clonic. The patient claimed to be compliant on an unknown dose of carbamazepine and phenobarb, which he received at a peripheral clinic.
According to his family the patient had a normal development as a young child, but at the age of 12 he developed a malar rash, and all developmental progression seized. This developmental delay was never brought under the attention of any health worker.
On examination the patient was in a good general condition, with normal vital signs. A malar rash was evident. He had an abnormally short stature of 149 cm, no secondary sexual characteristics, and had only a right sided palpable testis. Systemic examination, including neurological, was within normal limits.
The patient was admitted, and his seizures were well controlled on carbamazepine 200mg tds orally. Early during his stay he had a seizure while taking a bath, and subsequently sustained 10% body surface area burns, which necessitated a skin graft and physiotherapy.
Later during his stay the patient had aggressive outbursts during which he assaulted a patient and threatened a health worker. At that time his seizures were well controlled, his wounds were healing well, and he expressed that he wishes to be discharged. Unfortunately the patient was lost to follow-up.
Summary of special investigations done during admission:
Hypogonadism, a common but frequently underdiagnosed entity, is defined as a combination of abnormal serum testosterone levels and the presence of insufficient androgen end-organ tissue effect1. This diagnostic entity is characterized by an abnormal decrease in the functional capability of the gonads. This results in the delay of growth and sexual development. Primary or hypergonadotropic hypogonadism is characterized by sex organ failure2.This discussion focuses on secondary or hypogonadotropic hypogonadism, which has many central causes:
The hypothalamo-pituitary-gonadal axis can be interrupted by the mass effect of tumours because of spatial encroachment and compressions of the portal vessels. The resultant effect is less GnRH reaching the pituitary gland via the portal vessels. Craniopharyngiomas, the most common suprasella turcica tumour in children, are slow growing, and might only be diagnosed in early adulthood, presenting with amenorrhea, gonadotropin deficiency, hyperprolactinemia, obesity, ocular defects, and recurrent frontal headaches with vomiting2.
When prepubertally acquired male hypogonadism presents with scanty body and terminal facial hair, high pitched voice, female distribution of pubic hair, small testis, small penis, little or no scrotal rugae, small prostate, and eunuchoidal proportions1.
The evaluation of hypogonadism includes the measurement of pituitary function. Thyroid and adrenal function should also be evaluated4. A good understanding of the classification of hypogonadism is needed for the interpretation of blood results.
Imaging of the pituitary region is indicated when an organic cause is suspected. MRI is superior to CT in detecting smaller lesions, and is the imaging modality of choice. CT is adequate for detecting macro adenomas, and is a less expensive imaging option1.
Our patient does not have a definitive diagnosis of systemic lupus erythematosus (SLE). Nevertheless, this remains an interesting avenue to explore. Neuropsychiatry SLE is seen in 20% to 70% of SLE patients. Seizures, in particular, occur in 10% to 40% of paediatric cases, with generalized seizures being more common than focal seizures5.
It was shown that 88.3% of SLE patients have at least one seizure.14 The incidence of epilepsy in patients with systemic lupus erythematosus is raised to between 5.4%-10%.6,7,8 The seizures tend to respond to anticonvulsant drugs, and can take any form7, with various EEG abnormalities reported.6,7,9 Epilepsy is particularly common in association with the presence of anticardiolipin antibodies, especially in high titre6,7 the lupus anticoagulant6,10; and the antiphospholipid antibody syndrome(APS).8,9 However, these findings are not universal.8,11Brain MRI tends to be normal in those with epilepsy alone7but abnormal in those with clinical features of the APS.12 In another study of patients with systemic lupus erythematosus (SLE) admitted to hospital, an association of epilepsy with stroke (clinical or on imaging) was reported.9
The role of these antiphospholipid antibodies in causing epilepsy has been open to debate. Possible mechanisms include a direct effect of antibodies causing seizures, the trapping of immune complexes within vessels resulting in seizures, and antiphospholipid antibodies causing microvascular lesions. The direct effect of antibodies in provoking epilepsy is supported by studies showing that antibrain antibodies can directly cause seizures13; that serum from patients with SLE with epilepsy and anticardiolipin antibodies can inhibit Cl currents through the GABA receptor complex14; and that the presence of anticardiolipin antibodies in the CSF is longitudinally associated with clinical symptoms.15 The finding that antiphospholipid antibodies react directly with CNS tissue16 does not rule out secondary damage as a mechanism for seizures. Ischemia-induced seizures secondary to a hypercoaguable state is backed by reports of abnormal imaging and an association with stroke as a confounding factor in some groups of patients. Even in the presence of normal imaging, post-mortem has disclosed cerebral microinfarctions.7 Many patients with SLE and epilepsy have no detectable antiphospholipid antibodies in the serum or the CSF, so other processes such as infection, metabolic abnormalities, or as yet unidentified antibodies could be responsible. It is of interest that anti-GM1 antibodies, reported to be epileptogenic, have been identified in 15.5% of patients with systemic lupus erythematosus.17 More information can be found on the Palace's article18
Appenzeller et al19 observed epileptic seizures in 11.2% of SLE patients. Antiphospholipid antibodies and stroke were related to epileptic seizures at SLE disease onset. Patients with renal flares, epileptic seizures at SLE disease onset, and antiphospholipid antibodies were at greater risk for acute symptomatic seizures during follow-up. Recurrence of epileptic seizures occurred in 1.3% of patients and was associated with antiphospholipid syndrome.
The antiphospholipid syndrome (APS) is defined by the presence of antiphospholipid antibodies (aPL), demonstrated by ELISAs for antibodies against phospholipids and associated phospholipid-binding cofactor proteins and/or a circulating lupus anticoagulant (LA), together with diverse systemic clinical manifestations such as thrombosis, and recurrent spontaneous abortions. According to the criteria set out in Sydney the only neurological manifestations that can be suitable as APS classification criteria are ischemic events (stroke and transient ischemic attacks). However, other neurological manifestations, including seizures in particular, have been repeatedly reported in APS patients20.
Cytokines are also linked to the neuropsychiatry manifestations of SLE, including seizures21. It is suggested that pro-iflammatory cytokines are locally produced in the CNS, since the levels of IL-6 and interferon-? are higher in the CSF than in the plasma of patients with neuropsychiatry SLE. Many other mediators of inflammation are also suspected. Flares of SLE have also been linked to hyperestrogenic states22.
Testosterone replacement, as indicated in hypogonadism, shifts the cytokine balance to a reduced state of inflammation in hypogonadotropic males23. This treatment is an exiting possibility that could have addressed our patient's pathology on more than one level.
We agree that gonadal function, both in men and women, is seriously affected in a variety of acute and chronic diseases. In most cases, the pathophysiological mechanisms are hypothalamic dysfunction in conjunction with direct gonadal involvement. Hormonal changes in acute illnesses rarely reach the stage of inducing clinical manifestations and they are reversible in the majority of cases, following regression of the main disease. In chronic illnesses, like cirrhosis and end-stage renal disease, and in our case hormonal changes itself, provoke severe systemic manifestations and worsen prognosis. In these cases, the correction of hypogonadism neither affects the progress of the disease nor improves prognosis24.
From our knowledge this combination of clinical SLE, hypogonadotrpic hypogonadism, and epilepsy is an uncommon presentation which requires a multidisciplinary approach.
Bardet-Biedl syndrome http://www.nlm.nih.gov/mesh/jablonski/syndromes/syndrome048.html
Kallmann´s syndrone http://www.medstudents.com.br/endoc/endoc1.htm
Laurence-Moon syndrome http://www.nlm.nih.gov/mesh/jablonski/syndromes/syndrome393.html
Pituitary Apoplexy http://www.emedicine.com/OPH/topic471.htm
Prader-Willi syndrome http://www.emedicine.com/ped/topic1880.htm
Turner Syndrome http://www.emedicine.com/ped/topic2330.htm
The authors wish to thank Dr. Greg Hough for his advice regarding the preliminary investigations done, and Ben-Barend Grib for his technical assistance with the writing of this case report.