#217 Restless Leg Syndrome

FAST FACTS AND CONCEPTS #217

RESTLESS LEG SYNDROME

Jennifer Johnson MD, PhD and Robert Arnold MD

Background Restless Leg Syndrome (RLS) is a neurologic disorder characterized by unpleasant sensations in the legs causing an uncontrollable urge to move when at rest in an effort to relieve those feelings. Between 2-15% of the population have RLS, with a peak incidence between 40 and 60 years of age and a 1:2 male:female ratio. It occurs more frequently in end-stage renal disease patients on chronic hemodialysis (up to 60%, depending on the series), and in patients with Parkinson’s disease (up to 20%) than in the general public. RLS disrupts sleep, can lead to excessive daytime sleepiness, depression, and a decreased quality of life. This Fast Fact will review its evaluation and management.

Causes The etiology of primary RLS is unknown although it is thought to be a genetic disorder involving either central or peripheral dopaminergic pathways. Common secondary causes of RLS are polyneuropathies; diabetes mellitus; rheumatologic diseases such as rheumatoid arthritis, Sjogren’s syndrome, and fibromyalgia; renal failure; pregnancy; iron deficiency; and hypo- or hyperthyroidism. Drugs including nicotine, caffeine, alcohol, 2^nd generation antidepressants such as SSRIs and SNRIs, neuroleptic agents, dopamine-blocking antiemetics such as metoclopramide, and sedating antihistamines are all known to worsen RLS symptoms.

Symptoms and Diagnosis The International RLS Study Group and the National Institutes of Health (NIH) criteria for diagnosis include: (1) an urge to move the legs, (2) temporary relief with movement, (3) onset or worsening of symptoms with rest or inactivity, and (4) worsening or onset of symptoms in the evening or night (3). Patients describe symptoms of trouble falling asleep, trouble getting back to sleep, "a funny feeling in the legs," or a "creepy or crawly feeling in the legs." Patients or their bed partners may also report ‘periodic limb movements of sleep’: stereotyped, repetitive flexion movements (‘jerking’) of the legs and occasionally arms, exacerbated when patients lie down for prolonged periods. RLS is a clinical diagnosis for which there is not a confirmatory diagnostic test. It should be differentiated from akathisia, a constant and generalized feeling of motor restlessness not associated with leg discomfort or rest. It can be differentiated from peripheral neuropathies, lumbosacral radiculopathy, and ordinary leg cramps by its circadian rhythm, relief with movement, and the prominence of pain symptoms in non-RLS syndromes.

Treatment Address any treatable secondary causes of RLS (e.g. with iron repletion or levothyroxine) and work with patients to avoid drugs and medications known to aggravate RLS. Distraction activities such as playing video games or crossword puzzles can decrease symptoms during wakeful periods. Drug treatment is recommended for patients who have not improved despite conservative interventions or who have persistent, distressing symptoms. Given the paucity of studies comparing different drugs, experts recommend the following (14):

· Dopamine agonists: The most frequently used drugs are the dopamine agonists, pramipexole and ropinirole. Both have been determined to be effective in industry-funded, double-blind, placebo-controlled studies (7, 8). Doses as low as 0.125 mg of pramipexole at bedtime or 0.25 mg of ropinirole are effective in improving sleep and decreasing discomfort in mild-to-moderate cases. Doses of greater than 0.75 mg/day of pramipexole or 4 mg/day of ropinirole are of unproven benefit. Side effects are usually mild, transient, and limited to nausea, lightheadedness, and fatigue. Both drugs cost roughly $100 (US) a month at the starting dose. While there are small series showing the effectiveness of levodopa/carbidopa, experts have recommended it only be used for intermittent RLS because of worries that levodopa may cause augmentation, rebound, or recurrence of symptoms. Finally, cabergoline, a dopamine agonist with a long half life may be useful for patients who experience rebound symptoms with shorter acting agents, although it is not FDA approved for this purpose.

· Other agents: There are small studies indicating that benzodiazepines (9), opioids (10), and select anticonvulsants such as gabapentin and carbamazepine (11, 12, 13) are effective in RLS. Expert opinion, however, generally recommends these drugs as second line agents due to the paucity of data supporting their use relative to dopamine agonists, side effects, and risk of abuse.

References

1. Phillips B, Young T, Finn L, et al. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000; 160:2137-2141.
2. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med. 2004; 5:293-299.
3. Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003; 4:101-119.
4. Connor JR, Wang XS, Patton SM, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004; 62:1563-1567.
5. Pittock SJ, Parrett T, Adler CH, et al. Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Mov Disord. 2004; 19:695-699.
6. Silber MH, Richardson JW. Multiple blood donations associated with iron deficiency in patients with restless legs syndrome. Mayo Clin Proc. 2003; 78:52-54.
7. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology.1999; 52:938-943.
8. Adler CH, Hauser RA, Sethi K, et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology. 2004; 62:1405-1407.
9. Peled R, Lavie P. Double-blind evaluation of clonazepam on periodic leg movements in sleep. J Neurol Neurosurg Psychiatry. 1987; 50:1679-1681.
10. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005; 20:345-348.
11. Telstad W, Sorensen O, Larsen S, et al. Treatment of the restless legs syndrome with carbamazepine: a double blind study. BMJ. 1984; 288:444-446.
12. Garcia-Borreguero D, Larrosa O, de la Llave Y, et al. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002; 59:1573-1579.
13. Eisensehr I, Ehrenberg BL, Rogge Solti S, Noachtar S. Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazide. J Neurol. 2004; 251:579-583.
14. Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004; 79(7):916-22.

Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

#216 Asking About Cultural Beliefs in Palliative Care

FAST FACTS AND CONCEPTS #216

Asking about cultural beliefs in palliative care

Hillary Lum MD, PhD and Robert Arnold MD

Background Patients’ cultural backgrounds profoundly influence their preferences and needs regarding discussing bad news, decision-making, and the dying experience. This Fast Fact offers a framework for taking a ‘cultural history’ to better understand a patient’s and family’s needs. See also these related Fast Facts: #17 (illness experience), #19 (spiritual history), #26 (explanatory model), #183/184 (conflict resolution).

C – Communication. Identify the patient’s preferences regarding how and to whom medical information is shared. Some people want to know everything about their medical condition, and others do not. How much would you like to know? For those who request that the physician discuss their condition with family members: Would you like me to speak with them alone, or would you like to be present? Identify main contacts to give information to about the patient’s condition. Carefully explore with families requests to hide information from a patient (see references 4 and 5) – a future Fast Fact will address this topic in more detail.

U – Unique cultural values. Use respectful, curious, and open-ended questions about a patient’s cultural heritage to identify their values. Is there anything that would be helpful for me to know about how you and your family view serious illness? Are there cultural beliefs, practices, or preferences that affect you during times of significant illness? If the patient is open to discussing death: What concerns do you have about dying? Are there things that are important to you or your family that I should know about?

L – Locus of decision-making. For some patients medical decision-making is communally driven rather than individualistic. Multiple family members or a community elder or leader may need to be involved, often without prior official documentation because it is assumed or understood from the patient’s perspective. Do you prefer to make medical decisions about tests and treatments yourself, or would you prefer that others in your family or community make them for you?

T – Translators. Language barriers are extremely challenging, especially during times of severe illness. Utilize medical interpreters frequently and effectively. Refer to Fast Fact #154 for a detailed discussion on using interpreters in palliative care.

U – Understanding the patient and learning as a provider. Reassess what is being heard, understood, and agreed upon frequently, from both the patient’s and clinician’s standpoint. Specifically confirm the patient’s understanding or agreement (beyond nodding or “yes” responses). This is particularly important if a medical translator is involved as miscommunication is common even when using trained medical interpreters – see reference (6). Can you tell me – in your own words – what you have heard from me and what’s most important to you about what I’ve said?

R – Ritualized practices and restrictions. Determine if there are specific customs the patient desires to be followed. These must be communicated to other health care providers, especially in the hospital setting. It may be necessary to advocate for the patient and negotiate with healthcare facility administrators to find an agreeable way to honor a patient’s wishes. Are there specific practices that you would like to have in the hospital or at home? Are there aspects of medical care that you wish to forgo or have withheld because of your cultural beliefs? Is anything discouraged or forbidden? If the patient is approaching death, and willing to discuss it: Are there specific practices that are important to you at the time of death or afterwards that we should know about?

E – Environment at home. Given that a majority of hospice care happens in the patient’s home environment, respectfully explore whether there are any needs that can be met by the health care system, and how open the patient, family or community is to receiving care at home. Recognize that patients may be hesitant to voice needs, or resistant to accepting help from outside the community. Even if a trusting, collaborative relationship has developed between a patient/family and clinicians in the hospital, this may not immediately translate into the home setting. With the patient’s permission, expectations about cultural-specific aspects of a patient’s care should be explicitly communicated to care providers outside the hospital.

References

1. Searight HR, Gafford J. Cultural Diversity at the End of Life: Issues and Guidelines for Family Physicians. Am Fam Phys. 2005; 71 (3)
2. Crawley LM, et al. Strategies for Culturally Effective End-of-Life Care. Ann Internal Med. 2002; 136:673-679.
3. Maugans TA. The SPIRITual History. Arch Fam Med. 1997; 5:11-16.4. Arnold R. Palliative Care Case of the Month: The Family Says Not to Tell. University of Pittsburgh Institute to Enhance Palliative Care. May 2006. Available at: http://www.dgim.pitt.edu/SPC/cases/May 06.doc.

5. Hallenbeck J, Arnold R. A request for non-disclosure: don’t tell mother. J Clin Oncol. 2007; 25(31):5030-4.
6. Pham K, et al. Alterations During Medical Interpretation of ICU Family Conferences That Interfere With or Enhance Communication. Chest. 2008; 134(1):109-116.

Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

#215 Opioid-Poorly Responsive Cancer Pain

FAST FACTS AND CONCEPTS #215

Opioid Poorly-Responsive Cancer Pain

Tamara Sacks MD, David E Weissman MD, and Robert Arnold MD

Background Relief of cancer pain from opioids is rarely all or nothing; most patients experience some degree of analgesia alongside opioid toxicities. When the balance of analgesia versus toxicity tips away from analgesia, the term ‘opioid poorly-responsive pain’ is invoked. While opioid poorly-responsive pain is not a discreet syndrome, it is a commonly encountered clinical scenario. This Fast Fact reviews key points in its assessment and management.

Differential Diagnosis of Opioid Poorly-Responsive Pain

1. Cancer-related pain

a. Cancer progression (new fracture at site of known bone metastases).

b. Causes of pain (eg. neuropathic pain, skin ulceration, rectal tenesmus, muscle pain) that are known to be less responsive to systemic opioids or opioid monotherapy.

c. Psychological/spiritual pain related to the cancer experience (existential pain of impending death).

2. Opioid pharmacology/technical problems

a. Opioid tolerance (rapid dose escalation with no analgesic effect).

b. Dose-limiting opioid toxicity (sedation, delirium, hyperalgesia, nausea – see Fast Facts #25, 142).

c. Poor oral absorption (for PO meds) or skin absorption (e.g. transdermal patch adhesive failure).

d. Pump, needle, or catheter problems (IV, subcutaneous, or spinal opioids).

3. Non-cancer pain

a. Worsening of a known non-cancer pain syndrome (diabetic neuropathy).

b. New non-cancer pain syndrome (dental abscess).

4. Other psychological problems

a. Depression, anxiety, somatization, hypochondria, factitious disorders.

b. Dementia and delirium both can effect a patient’s report of and experience of pain.

c. Opioid substance use disorders or opioid diversion.

Management Strategy

1. Initial Steps

a. Complete a thorough pain assessment including questions exploring psychological and spiritual concerns. If substance abuse or diversion is suspected, complete a substance abuse history (see Fast Facts #68, 69).

b. Complete a physical examination and order diagnostic studies as indicated.

c. Escalate a single opioid until acceptable analgesia or unacceptable toxicity develop, or it is clear that additional analgesic benefit is not being derived from dose escalation. If this fails, consider:

i. Rotating to a different opioid (e.g. morphine to methadone).

ii. Changing the route of administration (e.g. oral to subcutaneous).

d. Treat opioid toxicities aggressively.

e. Use (start or up-titrate) adjuvant analgesics, especially for neuropathic pain syndromes.

f. Integrate non-pharmacological treatments such as behavioral therapies, physical modalities like heat and cold, and music and other relaxation-based therapies – see Fast Fact #211.

2. Additional steps – Pain refractory to the initial steps requires multi-disciplinary input and care coordination.

a. Hospice/Palliative Medicine consultation to optimize pain assessment, drug management, and assessment of overall care goals.

b. Mental health consultation for help in diagnosis and management of suspected psychological factors contributing to pain.

c. Chaplain/Clergy assistance for suspected spiritual factors contributing to pain.

d. Interventional Pain and/or Radiation Oncology consultation.

e. Rehabilitation consultations (Physiatry, Physical and Occupational Therapy) to maximize physical analgesic modalities.

f. Pharmacist assistance with drug/route information.

References

1. Mercadante F, Portenoy RK. Opiate Poorly Responsive Cancer Pain Parts 1-3. J Pain Symptom Management. 2001; 21(2):144-150, 21(3):255-264, 24(4):338-354.

2. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002; 20(19):4040-9.

3. Fallon M. When morphine does not work. Support Care Cancer. 2008; 16(7):771-5.

4. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews. 2004, Issue 3. Art. No.: CD004847. DOI: 10.1002/14651858.CD004847.

5. Hanks GW. Opioid-responsive and opioid-non-responsive pain in cancer. Br Med Bull. 1991; 47(3):718-31.

6. Hanks G, Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scand.1997; 41:154-158.

Author Affiliations: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (TS, RA), and Medical College of Wisconsin, Milwaukee, Wisconsin (DEW).

#214: Prognosis in HIV Associated Malignancies

FAST FACTS AND CONCEPTS #214

PROGNOSIS IN HIV ASSOCIATED MALIGNANCIES

Steven Oppenheim MD

Background Fast Fact #213 introduced prognostic principles in HIV/AIDS, as well as gave survival data for many life-threatening complications of HIV infection. This Fast Fact presents survival data for malignancies commonly arising in the setting of HIV/AIDS. Before applying these data to individual patients, consideration should be given to the prognostic principles in HIV/AIDS discussed in Fast Fact #213.

Prognostic Data

· AIDS related Kaposi’s sarcoma (KS), has become less common since the use of combination antiretroviral therapy (cART). It is a grossly violaeous spindle cell tumor, more common amongst men who have sex with men, and is associated with co-infection with human herpes virus-8. KS can involve the skin, mucous membranes, and viscera. Some patients with mild to moderate KS may have complete resolution of their disease with cART and/or chemotherapy. More extensive disease of the skin or viscera portends a poorer prognosis with a 2 year survival of 58%. A prognostic index has been developed for patients with KS on cART. In this index age > 50 years, developing KS as a later-stage complication of HIV infection (as opposed to KS being a patient’s first AIDS-defining illness), CD4 cell count <100 style=""> Patients with all 4 poor markers had a 1 year survival of ~40%.

· Primary CNS lymphoma is strongly associated with Epstein Barr virus infection. Treatments include cART, whole brain radiation and chemotherapy. Median survival was 3 months before the use of cART, but has improved to16 months for those responding to cART (with ≥ 50 CD4 cell count increase over their baseline count or ≥ 0.5log10* HIV viral load decrease after lymphoma diagnosis).

· Systemic non-Hodgkin’s Lymphoma (Diffuse Large Cell Lymphoma - DLCL) is the most common lymphoma associated with HIV infection. A decreased incidence has not been observed with cART, although survival in HIV patients is now approaching that of DLCL patients without HIV. 5 year survival with current chemotherapy regimens is approximately 50%. A well-validated tool for stratifying DLCL survival is the International Prognostic Index (IPI) which includes age, tumor stage, serum LDH, performance status, and number of extranodal disease sites. Patients with intermediate-risk IPI scores have a 50-64% 3 year survival. However patients with high-risk IPI scores have only a 13% 3 year survival, even in the cART era (see references 3, 9).

· Squamous cell carcinoma (SCC) of the cervix is seen frequently in patients with HIV and is caused by the human papilloma virus. Survival data are limited for HIV infected patients, but it appears to be similar to patients without HIV infection and is unaffected by the use of or response to cART. Five year survival of SCC of the cervix is 86% for locally invasive disease, 43% with regional disease, and 11% with metastatic disease.

· Squamous cell carcinoma (SCC) of the anus, while not officially an AIDS-defining malignancy, is 120 times more common in HIV infected than non-infected patients and is also associated with human papilloma virus infection. Survival does not seem to be affected by HIV status, with overall 2 year survival in the ~75% range.

* 0.5 log10 decrease equals, for instance, a decrease of 4.0 to 3.5 log10, or 10,000 to 3,160 copies HIV-RNA/ml.

References

1. Bernstein WB, Little RF, Wilson WH, Yarchoan R. Acquired Immunodeficiency Syndrome-related malignancies in the era of highly active antiretroviral therapy. Int. J Hematology. 2006; 84:3-11.

2. Biggar RJ, Engles EA, Ly S, et al. Survival after cancer diagnosis in persons with AIDS. JAIDS. 2005; 39:293-299.

3. Bower M, Gazzard B, Mandalia S, et al. A prognostic index for systemic AIDS-related non-Hodgkin lymphoma treated in the era of highly active antiretroviral therapy. Ann Intern Med. 2005; 143:265-273.

4. Cheung MC, Pantanowitz L, Dezube BJ. AIDS Related Malignancies: Emerging challenges in the era of highly active antiretroviral therapy. The Oncologist. 2005; 10:412-426.

5. Chiao EY, Giordano TP, Richardson P, El-Serag HB. Human Immunodeficiency Virus-associated squamous cell cancer of the anus: Epidemiology and outcomes in the highly active antiretroviral therpy era. J Clin Onc. 2008; 26:474-479.

6. Hentrich M, Maretta L, Chow KU, et al. Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin’s disease: results of a multicenter study. Ann Oncology. 2006; 17:914-919.

7. Hoffmann C, Tabrizian S, Wolf E. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS. 2001; 15:2119-2127.

8. Goldie SJ, Weinstein MC, Kuntz KM, Freedberg KA. The costs, clinical benefits and cost-effectiveness of screening for cervical cancer in HIV-infected women. Ann Intern Med. 1999; 130:97-107.

9. Lim ST, Karim R, Tulpule A, Nathwani BN, Levine AM. Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy. J Clin Oncol. 2005; 23:8477-8482.

10. Mounier N, Spina M, Gisselbreght C. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haem. 2007; 136:685-698.

11. Oehler-Janne C, Huguet F, Provencher S, et al. HIV specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy. J Clin Onc. 2008; 26:2550-2557.

12. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS. 2003; 17:1787-1793.

13. Stebbing J, Sanitt A, Nelson M, Gazzard B, Bower M. A prognostic index for AIDS-associated Kaposi’s sarcoma in the era of highly active antiretroviral therapy. Lancet. 2006; 367:1495-1502.

14. Uronis HE, Bendell JC. Anal cancer: an overview. The Oncologist. 2007; 12:524-534.

Author Affiliation: San Diego Hospice at the Institute for Palliative Care, San Diego, California.

FAST FACTS AND CONCEPTS #213

PROGNOSIS IN HIV AND AIDS

Steven Oppenheim MD

Introduction The prognosis of patients with HIV/AIDS (Human Immunodeficiency Virus infection/Acquired Immune Deficiency Syndrome) has improved dramatically since 1996 for those who have access to appropriate treatment. Due to the success of combination antiretroviral therapy (cART) since 1996 as well as improvements in the prevention and treatment HIV complications, over 80% of patients are now alive 10 years after sero-conversion,. Deaths from opportunistic infections (OI) have declined while mortality from other co-morbidities has become more common (e.g. hepatitis B and C infection, renal failure, non-HIV-related cancers, cardiovascular disease, suicide, and complications of substance abuse). In fact, patients with CD4 counts >200 cells/mm3 are more likely to die from non-HIV-related illnesses than they are from complications of AIDS, at least over a time-frame of one decade. This Fast Fact discusses prognostication in patients who are suffering life-threatening complications related to HIV infection using data where cART was available. Fast Fact #214 will discuss prognosis specifically for malignancies arising in the setting of HIV infection.

Prognostic Principles

· Numerous factors affect prognosis such as age, remaining antiviral treatment options, opportunistic infections’ response to therapy, the development of untreatable complications, functional status, nutritional status, CD4 cell count, and HIV viral load.

· In the pre-cART era median survival for people with a CD4 count <>

· Due to the rapidly changing field of HIV medicine, close collaboration with the patient’s HIV provider is mandatory. While the following data are the best available they remain incomplete, may become outdated as therapies evolve, and should be applied to individual patients cautiously.

· Survival for all the HIV associated complications discussed in this Fast Fact has improved due to the use of cART.

Common causes of death in patients with HIV/AIDS with available survival data

· Disseminated mycobacterium avium complex infection: median survival is ~10 months with optimal therapy.

· Pneumocystis pneumonia: survival for all patients presenting is 80-90%. Short-term ICU survival is 75% in patients on cART and 37% not on cART.

· Disseminated cytomegalovirus infection (including retinitis): the largest prospective cohort study demonstrated a median survival of 35 months for all patients on cART compared with 8 months for those not using cART. Six month survival is 61-73% for patients not taking or not responding to cART, but 98% for patients with low CD4 counts who initiate and respond well to cART (CD4 count increases to over 50 cells/mm3).

· Toxoplasma encephalitis: 77-90% of patients are alive after 12 months if on cART, and most who die do so within 6 months of diagnosis. Persistence of altered mental status after initiation of therapy is a strong predictor of early death.

· Progressive multifocal leukoencephalopathy: median survival is ~11 months on cART, 4 months without cART. If cART is started after PML is diagnosed 1 year survival is 58% vs. 24% for those who develop PML already cART.

· AIDS Dementia complex: is caused by HIV and results in progressive cognitive, motor, and behavioral decline. The median survival is 40-81 months from the time of diagnosis; shorter if the CD4 cell count remains <200>5,000 copies/ml.

· AIDS wasting syndrome: is defined by the involuntary loss of >10% body weight along with fever not associated with an OI or neoplasm, and either chronic diarrhea or weakness. Patients with very low lean body mass index (mass in kilograms/height in meters squared) – less than 14.5kg/m2 – have a median survival of ~16 months. These data are from the mid-1990s and it is unclear if the prognosis has changed in the last decade. With unintentional weight loss which does not meet the syndrome definition (loss of 5-10% body weight) there is still a four-fold increased risk of death over 6 months.

References

1. Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: Data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol. 2003; 9(suppl 1):47-53.

2. Antinori A, Larussa D, Cingolani A et al. Prevalence, associated factors and prognostic determinants of AIDS-related Toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy. Clin Infect Dis. 2004; 39:1681-1691.

3. Bhaskaran K, Hamouda O, Sannes M, et al. Changes in the Risk of Death After HIV Seroconversion Compared With Mortality in the General Population. JAMA. 2008; 300(1):51-59.

4. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leykoencephalopathy. Neurology. 1999; 52:623-625.

5. Coakley E, Samore M, Gillis J, et. Al. The values of quantitative serum HIV-1 RNA levels and CD4 cell counts of <50 x 10 6 cells/L. AIDS. 2000; 14:1147-1153.

6. D’Avignon LC, Schofield CM, Hospenthal DR. Pneumocystis Pneumonia. Semin Respir Crit Care Med. 2008; 29(2):132-40.

7. Dore GJ, MvDonald A, Yueming L, et al. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS. 2003; 17:1539-1545.

8. Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive Multifocal leukoencephalopathy: Improved survival of human immunodeficiency virus-infected patients in the protease-inhibitor era. J Infect Dis. 1999; 180:621-625.

9. Gasnault J, Taoufik Y, Goujard C et al. Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J Neurovirol. 1999; 13:1426-1428.

10. Hoffmann C, Ernst M, Wolf E, et al. Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses. Clin Microbiol Infect. 2007; 13:510-515.

11. Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infectious Diseases. 2004; 4:557-565.

12. Kempen JH, Jabs DA, Wilson LA, et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis. 2003; 37:1365-1373.

13. Krentz HB, Kliewer G and Gill MJ. Changing mortality rates and causes of death for HIV-infected individuals living in Southern Alberta, Canada from 1998 to 2003. HIV Medicine. 2005; 6:99-106.

14. MacArthur RD, et.al. Comparison of prognostic significance of latest CD4 cell count and HIV RNA levels in patients with advanced HIV infection on highly active antiretroviral therapy. HIV Clin Trials. 2005; 6:127-135.

15. Melchior JC, Niyongabo T, Henzel D, Durack-Bown J, Boulier A. Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition. 1999; 15:865-869.

16. Mikaelsson L, Jacobson G, Andersson R. Pneumocystis pneumonia: a retrospective study 1991-2001 in Gothenburg, Sweden. J Infect. 2006; 53:260-265.

17. Moore RD, CHaisson RE. Natural history of opportunistic disease in an HIV infected urban clinical cohort. Ann Intern Med. 1996; 124:633-642.

18. Morris A, Wachter RM, Luce J, Turner J and Huang L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS. 2003; 17:73-80.

19. Selwyn PA, Forstein M. Overcoming the False Dichotomy of Curative vs Palliative for Late-Stage HIV/AIDS “Let me live the way I want to live, until I can’t”: JAMA. 2003; 290:806-814.

20. Shen JM, Blank A, Selwyn PA: Predictors of Mortality for Patients with Advanced Disease in an HIV Palliative Care Program: J AIDS. 2005; 40:445-447.

21. Shetty SM, Vanston VJ, Alexander C. The Hospice and Palliative Medicine Approach to Caring for Patients with HIV/AIDS. UNIPAC-7, 3^rd Ed. American Academy of Hospice and Palliative Medicine. 2008.

22. Tang AM, Forrester J, Spieglman D, et al. Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. JAIDS. 2002; 31:230-236.

23. Tozzi V, Balestra P, Serraino D, et al. Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART. AIDS Res Human Retrov. 2005; 21:706-713.

24. The Antiretroviral Therapy (ART) Cohort Collaboration. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007; 21:1185-1197.

25. The CASCADE Collaboration. Effective Therapy has altered the spectrum of cause-specific mortality following HIV-seroconversion. AIDS. 2006; 20: 741-749.

26. Welch K, Morse A, et al. The clinical profile of end-stage AIDS in the era of highly active antiretroviral therapy. AIDS Pt Care and STDs. 2002; 16:75-81.

Author Affiliation: San Diego Hospice at the Institute for Palliative Care, San Diego, California.