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Alpers disease

Alpers' disease, also called progressive infantile poliodystrophy, is a progressive degenerative disease of the central nervous system that occurs in infants and children. It is an autosomal recessive disorder that is sometimes seen in siblings. First signs of the disease, which include intractable seizures and failure to meet meaningful developmental milestones, usually occur in infancy, after the first year of life, but sometimes as late as the fifth year. more...

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Primary symptoms of the disease are developmental delay, progressive mental retardation, hypotonia (low muscle tone), spasticity (stiffness of the limbs) possibly leading to quadriplegia, and progressive dementia. Seizures may include epilepsia partialis continua, a type of seizure that consists of repeated myoclonic (muscle) jerks. Optic atrophy may also occur, often leading to blindness. Deafness may also occur. And, although physical signs of chronic liver dysfunction may not be present, many patients suffer liver impairment leading to liver failure. While some researchers believe that Alpers' disease is caused by an underlying metabolic defect, no consistent defect has been identified. Pathologically, there is status spongiosus of the cerebral grey matter.


There is no cure for Alpers' disease and, currently, no way to slow its progression. Treatment is symptomatic and supportive. Anticonvulsants may be used to treat the seizures. However, caution should be used when selecting valproate as therapy since it may increase the risk of liver failure. Physical therapy may help to relieve spasticity and maintain or increase muscle tone.


The prognosis for individuals with Alpers' disease is poor. Those with the disease usually die within their first decade of life. Liver failure is usually the cause of death, although cardiorespiratory failure may also occur.


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A preliminary report on basal & stimulated plasma cortisol in patients with acquired immunodeficiency syndrome
From Indian Journal of Medical Research, 11/1/00 by Bhanasali, A

Background & objectives Structural and/or functional alterations in adrenal glands have been reported in human immunodeficiency virus (HIV) infection. However, no information has been reported from India. Hence a study was undertaken to assess the basal and circadian variations in plasma cortisol, and cortisol response to bolus ACTH in patients with AIDS.

Methods: Basal and stimulated plasma cortisol levels at 0800 h and 1600 h and, at 30 and 60 min following an intravenous bolus of 250 Rg ACTH (short synacthen test, SST) were estimated in 15 patients with AIDS (CD4

Results: The patients had higher median basal plasma cortisol levels as compared to the controls at 0800 h (540 nmol/ vs 415 nmol/l, P550 nmol/1) to SST. The lone patient with subnormal cortisol response had no feature of adrenal insufficiency. On the contrary, 3 patients clinically suspected to have adrenal insufficiency, had normal plasma cortisol response.

Interpretation & conclusions: These findings suggest that most patients with AIDS have elevated basal plasma cortisol levels with abnormal circadian rhythm in some and normal adrenocortical reserve irrespective of the symptoms/signs of adrenal insufficiency.

Key words Adrenocortical function-HIV-short synachten test

Structural and/or functional alterations in various endocrine glands have been observed in the early and late stages of HIV infection'. The adrenal glands had received a great deal of attention because of similarities in the clinical presentation of acquired immunodeficiency syndrome (AIDS) and adrenal insufficiency2 and, its frequently observed involvement (up to 70%) at autopsy'. However, tissue destruction (>90%) sufficient to cause adrenal insufficiency in these patients is uncommon'. Adrenocortical function in patients with AIDS include normal or elevated basal plasma cortisol5-', normal or decreased plasma adrenocorticotropin (ACTH)'-', loss of circadian rhythm in cortisol and ACTH secretion',', subnormal cortisol response to ACTH`-9, peripheral glucorticoid resistance"', and negative correlation of plasma cortisol with CD4 cell count'. No study however, has been reported from India where HIV infection is fast-emerging as a major health hazard and opportunistic infections in these patients are substantially different from that in the West",12.

We report our observations on the basal and circadian variation in plasma cortisol and, cortisol response to bolus ACTH in patients with AIDS.

Material & Methods

Fifteen consecutive patients (12 men, 3 women) with AIDS seen at the Nehru Hospital, Postgradute Institute of Medical Education and Research (PGIMER), Chandigarh between August 1998 and June 1999 were included in this study. The diagnosis of AIDS was based on WHO criteria 13. Two sequential ELISA tests using UBI (United Biochem Inc, USA) and DETECT (Biochem Immunosystem, Canada) kit and a rapid test using Immunocomb kit (Organic, Israel)-were performed in all patients. In case of discordant results, a Western blot was performed to confirm the diagnosis. CD4 cell count was carried out by flow cytometry using monoclonal antibodies (Becton Dickinson, USA). Appropriate body secretions were microbiologically tested to determine the nature of opportunistic infections. Patients receiving ketoconazole, phenytoin, glucocorticoids, rifampicin and isonicotinic acid hydrazide were excluded. The median age of the patients was 33 yr (range 15-52) and median body mass index (BMI) was 16.3 kg/ml (range 11.8 to 19.5). HIV infection was acquired through heterosexual contact in 13, including 3 women who were infected by their spouse and blood transfusion and iv drugs abuse one in each. Adrenal insufficiency was suspected when five of the following features were present: weight loss, general weakness, anorexia, diarrhoea, melanosis, postural hypotension, hyponatraemia and hyperkalaemia.

The control group included 12 HIV negative blood donors (10 men and 2 women). Their median age was 33 yr (range 27-38) and median BMI 23.4 kg/ml (range 18.8 to 25).

Blood. samples were collected at 0800 h and 1600 h on day 2 of admission for estimation of basal cortisol. Cortisol response to intravenous 250 gg cosyntropin (Synacthen, Ciba Geigy) was determined on day 3 at 0800 h, and venous blood samples collected at 0, and 30 and 60 min after injection of the ACTH bolus.

Plasma cortisol was estimated by a specific radioimmunoassay 14 with lowest detection limit of 37 nmol/l and intra-and inter-assay coefficient of variation of

Results were expressed in median with the range. Statistical analysis between two groups was determined by Mann Whitney U test. The values were considered significant at P


The control subjects were age matched with patients. Median BMI of the patient group was significantly lower (P550 nmol/1 to bolus ACTH. The patient (# 2) with subnormal cortisol response had non-Hodgkins lymphoma but showed no feature of adrenocortical insufficiency, and had normal adrenals on contrast enhanced computerised tomography (CECT). Three patients (# 5,9,15) suspected to have adrenocortical insufficiency, responded normally to SST. The stimulated median cortisol responses to ACTH at 30 and 60 min in the patient and the control groups were comparable. The peak cortisol response was also comparable in both the groups. However, the delta (A) cortisol (peak-basal) response in the control subjects was higher (P


We observed higher plasma cortisol levels in patients with AIDS at 0800 h as well as at 1600 h as has also been observed by others6'. However, Verges et all reported a slightly elevated basal cortisol in asymptomatic HIV positive group and not in patients with advanced HIV disease. The abnormalities in cortisol circadian rhythm was observed in five (33%10) of our patients. Lortholary et al7 reported loss in circadian rhythmicity in cortisol secretion in 5 (23%) and that of ACTH in 7 (32%) of the 22 patients with advanced HIV disease.

The basal plasma cortisol in acutely ill, non HIV infected patients occurs as a measure of stress induced activation of hypothalamo-pituitaryadrenal axis. However, the increase in plasma cortisol in patients with HIV infection occurs more often without concomitant or preceding elevation in ACTH, suggesting a direct stimulation of the adrenal cortex, possibly by cytokines such as interleukin-1 (IL-1) and interferon -(x (IF-cc) 16 . Human immunodeficiency virus stimulates the production of ILA and tumour necrosis factor-et (TNF-(x) by macrophages. TNF-ct in turn stimulates the IL-1 production by macrophages. IL-1 may target the hypothalamo-pituitary-adrenal axis to augment cortisol secretion or it may directly stimulate the adrenal gland"-". Pituitary cells in culture release corticotropin in response to IL-119 and the adrenocortical cells produce more cortisol when cocultured with mononuclear cells, a response probably mediated by IL-I from the mononuclear cells". Further, a decrease in cortisol catabolism by abnormal fatty acid S2 ' and an increase in the peripheral resistance to cortisol due to impaired glucocorticoid receptor binding in patients with AIDS, may also contribute to the increase in circulating cortisol!%.

Although the peak cortisol response in the patients was comparable to that in the controls, the delta (A) cortisol response in the patient group was lower than that observed in the controls. This supports the contention that incremental response to ACTH stimulation is a poor indicator of adrenal reserve. An incremental response is often lower, when the basal secretion is maximal 1,22. Higher basal plasma cortisol in advanced HIV disease is an indicator of exaggerated adrenal response to maximal stress, and thereby, a decrease in delta (A) cortisol response". Only one of our patients (6.6%) had lower peak plasma cortisol response (

The common opportunistic infections in patients with AIDS in India include tuberculosis (54.8%), oropharyngeal candidiasis (40.3%) and interstitial pneumonitis (20.9%). Herpes zoster, cryptococcal meningitis and CNS toxoplasmosis are infrequent, compared to the reports from the West". Of the 15 patients, 9 (60%) had opportunistic infections with adrenotropic organisms. These include Mycobacterium tuberculosis in 5, Pneumocystis carinii in 2 and Cryptococcus neoformans and Histoplasma capsulatum, one each. All of them had a normal peak cortisol response (> 550 nmol/1) to bolus ACTH. The mere presence of adrenotropic opportunistic infections in these patients is not enough to induce clinical or subclinical adrenal insufficiency. Certainly, a large number of patients needs to be studied to reach a conclusion.

Our 3 patients, who fulfilled the criteria of clinical adrenal insufficiency, had normal peak cortisol response. Stolarczyk et al9 also reported comparable stimulated cortisol response in AIDS patients with or without symptoms of adrenal insufficiency.

We conclude that patients with AIDS with or without symptoms of adrenal insufficiency have normal adrenocortical reserve. A subnormal peak cortisol response to ACTH is an infrequent observation. Therefore routine glucocorticoid support to patients with AIDS is undesirable. Studies on a large group are required to consolidate these observations.

Reprint requests: Dr R.J. Dash, Professor & Head, Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012


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2. Greene LW, Cole W, Greene JB, Levy B, Louie E, Raphael B, et al. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med 1984: 101: 497-8.

3. Welch K, Finkbeiner W, Alpers CE, Blumenfeld W, Davis RL, Smuckler EA, et at. Autopsy findings in the acquired immunodeficiency syndrome. JAMA 1984; 252: 1152-9.

4. Freda PU, Wardlaw SL, Brudney K, Goland RS. Primary adrenal insufficiency in patients with the acquired immunodeficiency syndrome. A report of five cases. J Clin Endocrinol Metab 1994; 79: 1540-5.

5. Verges B, Chavanet P, Dosgres J, Vaillant G, Waldner A, Brun IM, et al. Adrenal function in HIV infected patients. Acta Endocrinol 1989; 121: 633-7.

6. Membreno L, Irony 1, Dere W, Klein R, Biglieri EG, Cobb E. Adrenocortical function in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1987; 65: 482-7.

7. Lortholary 0, Christeff N, Casassus P, Thobie N, Vevssier P, Trogoff B, et al. Hypothalamo-pituitary-adrenal function in human immunodeficiency virus-infected men. JClin Endocrinol Metab 1996; 81: 791-6.

8. Villette JM, Bourin P, Doinel C, Mansour 1, Fiet J, Boudou P, et al. Circadian variations in plasma levels of hypophyseal, adrenocortical and testicular hormones in men infected with human immunodeficiency virus. JClin Endocrinol Metab 1990; 70, 579-7

9. Stolarczyk R, Rubio SI, Smolyar D, Young IS, Poretsky L. Twenty four hour urinary free cortisol in patients with acquired immunodeficiency syndrome. Metabolism 1998; 47: 690-4.

10. Norbiato G, Bevilacqua M, Vago T, Baldi G, Chebat E, Bertora P, et al. Cortisol resistance in acquired immunodeficiency syndrome. J Clin Endocrinol Metab 1992; 74:603-13.

11. Bollinger RC, Tripathy SP, Quinn TC. The human immunodeficiency virus epidemic in India. Current magnitude and future projections. Medicine 1995; 74: 97-106.

12. Sircar AR, Tripathi AK, Choudhary SK, Misra R. Clinical profile

of AIDS: A study at a referral hospital. J Assoc Physicians India 1998; 46: 775-8.

13. World Health Organization. Provisional clinical care definition for AIDS. Wkly Epidemiol Rec 1986; 61: 72-3.

14. Dash RJ, England BG, Midgley AR Jr, Niswender GD. A specific non-chromatographic radioimmunoassay for human plasma cortisol. Steroids 1975; 26: 647-61.

15. Oelkers W. Adrenal insufficiency. N Engl J Med 1996; 335: 1206-12.

16. Grinspoon SK, Bilezikian JP. HIV disease and the endocrine system. NEnglJ Med 1992; 327:1360-5.

17. Merrill JE, Koyanagi Y, Chen ISY. Interleukin-I and tumor necrosis factor-ot can be induced from mononuclear phagocytes by human immunodeficiency virus type- binding of the CD4 receptor. J trol 1989; 63: 4404-8.

18. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W. Interlukin-I stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 1987, 238: 552-4.

19. Woloski BMRNJ, Smith EM, Meyer WJ III, Fuller GM, Blalock JE. Corticotropin releasing activity of monokines. Science 1985: 230:1035-7.

20. Whitcomb RW, Linehan WM, Wahl LM, Knazek RA. M6nocytes stimulate cortisol production by cultured human adrenocortical cells. J Clin Endocrinol Metab 1988; 66: 33-8.

21. Christeff N, Michon C, Goertz G, Hassid J, Matheron S, Girard PM, et al. Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients. Eur J Cancer Clin Oncol 1988. 24: 1179-83.

22. Grinspoon SK, Biller BMK. Laboratory assessment of adrenal insufficiency. J Clin EndocrinolMetab 1994; 79:923-31.

23. Mulhall BP, Fieldhouse S, Deam D. Adrenocortical lesions and HIV infection. Lancet 1988; 1: 1345.

A, Bhansali, R.J. Dash, A, Sud*, S. Bhadada, S. Sehgal** & B.R. Sharma

Departments of Endocrinology, * Internal Medicine & ** Immunopathology, Postgraduate Institute of Medical Eduation & Research, Chandigarh

Copyright Indian Council of Medical Research Nov 2000
Provided by ProQuest Information and Learning Company. All rights Reserved

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