Neurological Damage

“Raltegravir is an HIV integrase inhibitor…We report four cases of treatmentexperienced HIV-infected patients who experienced significant exacerbation of pre-existing depression temporally related to the start of raltegravir therapy…Patient 1 is a 54-year-old man with a long-standing history of bipolar disorder. His HIV treatment included efavirenz since 2004, without apparent adverse psychiatric effects. On 5 June 2007, he was doing well and his bipolar disorder was stable. He discontinued enfuvirtide and started raltegravir, 400 mg twice daily, on 20 June 2007. He was seen by his family doctor on 27 June reporting increased depression. His dose of valproic acid was increased by his psychiatrist. For the next month, he experienced severe depression to the point where he did not have ‘the strength to get out of bed’…”

“The drugs worked. Mackie said they at first caused a dangerous reaction that left him “out of his head” but eventually gave him more energy and confidence.”

“[Neurological/Psychiatric signs associated with hypersensitivity reactions are ] Headache, paraesthesia [Disordered or perverted sensation; a hallucination of any of the senses]…Studies in HIV-infected patients have shown good penetration of abacavir into the cerebrospinal fluid (CSF),”

“less common signs and symptoms of hypersensitivity [to abacavir and possibly lamivudine] include lethargy, myolysis [muscle fibre damage], edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia [Disordered or perverted sensation; a hallucination of any of the senses]”

“Cognitive performance measurements and viral load were obtained from HIV-1-seropositive individuals with cognitive-motor impairment entering a clinical trial before the introduction of highly active antiretroviral therapy (HAART). CSF [cerebro-spinal fluid] viral load was available from 179 patients, and peripheral (plasma or serum) viral load from 111 patients. Of these patients, 62% met the 1993 Centers for Disease Control (CDC) criteria for AIDS, and 19% had clinically significant cognitive impairment. Possible associations between viral load and cognitive scores were examined with general linear regression models with and without adjustment for age, education, study site, antiretroviral use, CD4 cell count, and CDC stage. RESULTS…No statistically significant associations emerged between either CSF or peripheral viral load and the global deficit score, or any of the seven cognitive domain deficit scores.”

“We present the 55-year-old woman who has had kidney transplantation three times. She has been treated with immunosuppressive therapy and lamivudine for hepatitis B and C. Nine years after the last transplantation she showed neurological symptoms that presented in the form of confusion and epileptic seizures of the grand mal type. A brain MRI showed large oval zones of hyperintense MR signal in T2-weighted image and hypointense in T1-weighted image around the frontal horns of the lateral ventricles, bilaterally and in both cerebellar hemispheres. After reduction in immunosuppression and the exclusion of lamivudine from therapy, the patient was stable with normal neurological status during the course of next five years. We start from the assumption that the concomitant use of cyclosporin with mycophenolate mofetil and lamivudine, despite normal concentrations of cyclosporin, might cause the accumulation of toxic metabolites and lead to neurotoxicity that mimics PML in a chronic viral environment.”

“Aptivus [tipranavir] co-administered with 200 mg Ritonavir has been associated with reports of both fatal and non-fatal intracranial hemorrhage…Use caution when prescribing APTIVUS/ritonavir in patients who may be at risk of increased bleeding or who are receiving medications known to increase the risk of bleeding…In in vitro experiments, tipranavir was observed to inhibit human platelet [blood cells responsible for clotting] aggregation at levels consistent with exposures observed in patients receiving APTIVUS/ritonavir.”

“This report presents a patient with myelopathy [spinal cord disease with obvious symptoms including weakness of the legs,stiffness of the lower extremities] secondary to HAART-associated lipodystrophy and spinal epidural lipomatosis (SEL) [fat accumulating in tumor-like masses in the spinal cord]…He has received antiretroviral treatment since January 1993, with a total of 10 regimens, including various nucleoside analogue reverse transcriptase inhibitors (didanosine, zidovudine, lamividine, stavudine, and abacavir), non-nucleoside analogue reverse transcriptase inhibitors (delavirdine, viramune), and protease inhibitors (ritonavir, saquinavir, nelfinavir, amprenavir). He experienced virological failure on some of these regimens as a result of noncompliance and the development of resistance. At the time of his presentation in June 2003 the patient was on a HAART regimen (started in March 2000) of 400 mg lopinavir/100 mg ritonavir (Kaletra) plus 300 mg zidovudine/ 150 mg lamivudine (Combivir) twice a day.”

“Delirium is one of the most commonly encountered neurologic impairments in HIV, with a prevalence as high as 40%. Although the condition can be effectively treated with pharmacologic agents, a thorough evaluation is often needed to determine the underlying cause, which may be an opportunistic infection, a metabolic disturbance, neurotoxicity from substance abuse or antiretroviral therapy, or drug toxicity…Psychiatric conditions are also frequently observed in the context of HIV infection. Anxiety disorders are present in about 17% to 36% of persons with HIV and AIDS, and adjustment disorder with anxious mood seems to be most prevalent. Other mood disorders, such as mania and hypomania, may occur either early or late in the course of HIV disease, and mania has been associated with antiretroviral treatment in patients with no previous psychiatric history…Psychosis may present in patients with HIV either as a preexisting condition or as a consequence of CNS infection with the virus. Patients can experience hallucinations, delusions, and gross distortions of reality”

“Nucleoside reverse transcriptase inhibitors (NRTIs) suppress human immunodeficiency virus (HIV) replication, but are often associated with mitochondrial toxicity…no [previous] investigation has examined the effects of these drugs on brain mitochondria of individuals living with HIV. The authors used proton magnetic resonance spectroscopy to evaluate NRTI-related changes in brain mitochondria. N-acetylaspartate (NAA; sensitive to alterations in mitochondrial integrity) was measured in frontal lobe white and gray matter of 18 HIV+ individuals taking didanosine and/or stavudine (two NRTIs likely to cause mitochondrial toxicity), 14 HIV+ individuals taking zidovudine [AZT] and lamivudine [3TC], 16 HIV+ individuals not currently taking antiretrovirals, and 17 HIV- controls. The HIV+ groups were comparable on demographic measures, estimates of illness severity, and estimated length of HIV infection. Those taking didanosine and/or stavudine had a significant 11.4% decrease in concentrations of frontal white matter NAA compared to HIV- controls, whereas NAA levels of the other HIV+ groups were intermediate. Group differences in metabolites were not found in frontal gray matter. Lower levels of frontal white matter NAA were associated with longer periods of didanosine and/or stavudine treatment. Levels of NAA were not related to length of zidovudine/lamivudine treatment. Furthermore, taking more than one of stavudine, didanosine, and abacavir increased the likelihood of having reduced NAA. The results are consistent with previous studies finding HIV-related changes [or HIV-drug-related changes] in neuronal integrity. However, because NRTIs can injure mitochondria, we propose that the observed reductions in NAA in individuals taking didanosine and/or stavudine may be the result of depleted brain mitochondria and/or alterations in cellular respiration.”

“The authors report two cases of acute dystonic reactions [abnormal muscle tone, especially sudden spasms] as a side effect of lamivudine”

“This study will examine how HIV affects the brain and nervous system, learning, and behavior in children on highly active antiretroviral therapy (HAART). Although HAART has resulted in fewer HIV-infected children getting sick and even fewer dying from AIDS, many children on this treatment regimen develop significant brain or nervous system problems, such as learning difficulties, attention problems, hyperactivity, and depression [note how the study is phrased to ask "how HIV affects the brain and nervous system" although it's quite obvious that the investigators suspect that it is the drugs causing]”

“Although a causative relationship with brain pathology has not been clearly identified, a strong association between HIV encephalitis (HIVE) and the presence of APP has been confirmed in several studies…We analyzed archival brain tissues collected from 162 AIDS autopsies at UCSD and UCLA between 1983 and 2001…Immunostaining for ß-amyloid showed significant deposition in the frontal cortex of almost half of the AIDS brains studied. Similar but less abundant findings were observed in the hippocampus and occasionally in the basal ganglia…While the number of the cases studied with confirmed, consistent, long-term HAART is relatively low, a clear trend suggests increased ß-amyloid deposition in the HAART era”

“Primary cerebellar degeneration is still rare in HIV disease. HIV cerebellar syndromes are commonly caused by opportunistic infection, neoplasm, or encephalitis, and may be accompanied by cognitive impairment…We report a case of cerebellopontine atrophy in the setting of immune reconstitution.A 33-year-old HIV-positive man with a previously low absolute CD4 cell count and a high plasma viral burden achieved undetectable plasma virus levels on indinavir, lamivudine and stavudine. After 9 months, when his CD4 cell count had improved…he developed acute progressive ataxia [lack of coordination]. Within 4 months he was wheelchair bound. Concomitant nystagmus [involuntary oscillation of the eyeball], dysarthria [difficulty speaking], and dysdiadochokinesis [inability to execute rapidly alternating movements] suggested a cerebellar syndrome…Magnetic resonance imaging scans…indicated cerebellar atrophy 4 months later. Serology and cultures revealed no signs of opportunistic pathogens…The CD4 cell count continued to rise and the viral load remained undetectable until compassionate discontinuation of HAART. After discontinuing antiretroviral agents he died of an unrelated infection, with no change in the neurological findings.”

“Patients with the AIDS virus may have a higher risk of Alzheimer's disease, researchers said on [July 22, 2004]…Dr. Cristian Achim of the University of Pittsburgh and colleagues examined the brains of about 160 people infected with HIV…and found that two-thirds contained deposits of beta-amyloid protein similar to those seen in Alzheimer's patients. All the patients had been taking cocktails of drugs called highly active anti-retroviral therapy which are turning out to have unexpected effects on the body even as they hold the AIDS virus at bay…It was not clear whether the disease or the drug cocktails were the cause, he told an international meeting on Alzheimers”

“A severe neuromuscular weakness syndrome may occur in HIV-infected individuals. The association with hyperlactatemia [high lactic acid levels in the blood] and NRTI exposure supports mitochondrial toxicity as a pathogenesis.”

“The 4 children described in this article had vertically acquired HIV infection and mild or moderately symptomatic disease with stable immunologic and virologic parameters. All were on protease inhibitor-containing HAART regimens. Despite their stable disease and treatment with HAART, these patients had significant declines in neurocognitive functioning, although repeated testing can result in increases in cognitive scores attributable to practice effects. Thus, their significant drop in IQ scores within 6 to 12 months from the initiation of HAART is unusual and suggests CNS [central nervous system] involvement likely related to the effects of HIV on the developing brain. [Couldn't be the drugs!]”

“We report the case of a 40-year-old HIV-infected man who presented with the classic symptoms of a manic episode…The previously antiretroviral-naive patient had been started on a treatment regimen one month earlier that consisted of lopinavir/ritonavir and efavirenz…Efavirenz, a potent antiretroviral agent used to manage HIV-1 infection, is well known for its neuropsychiatric adverse effects…[in this case] it appears likely that the manic symptoms were caused by efavirenz, and at a therapeutic dose…[partially because of] the improvement of some of the symptoms, such as the pressured sppech and flight of ideas, when the patient stopped taking the efavirenz.”

“We present a case of psychosis in an individual with known HIV infection whose symptoms developed approximately 1 month following the commencement of combination antiretroviral therapy consisting of abacavir (ABC), nevirapine and combivir [AZT/Zidovudine plus 3TC/Lamivudine]. She presented with severe persecutory delusions, accompanied by mutism, posturing and catatonia. Following cessation of therapy and the introduction of a low-dose antipsychotic, her mental state resolved to a stable premorbid level, and no further disturbances of behaviour were noted. Furthermore, when re-challenged with the above combination minus ABC, there were no further episodes of psychosis. It is proposed that the aetiology of the psychosis was related to her antiretroviral therapy…The patient had been previously well [prior to taking antiviral drugs during pregnancy], with no previous medical or psychiatric history, apart from infection with HIV.”

“a study at San Francisco General Hospital…suggests a greater incidence rate of severe psychiatric illness resulting from HIV treatment with efavirenz than had previously been reported. "The serious side effects are suicidal depression including agitation, aggression and hallucinations," said Talia Puzantian, PharmD…Previous reports had stated that serious efavirenz side effects had less than a 2% incidence rate. Puzantian and co-authors questioned the rate after seeing a number of HIV patients on the drug admitted to the psychiatry unit, she said. The investigators undertook a retrospective study of severe psychiatric side effects and central nervous system side effects, comparing a database of HIV patients - from March 2000 to February 2002 - who had discontinued efavirenz with a group of patients who had discontinued nelfinavir…The study found that for HIV patients who had discontinued efavirenz because of side effects, the main problems were psychiatric and CNS [central nervous system] side effects, she said. Data showed that 18.3% of subjects on efavirenz reported vivid dreams; 14.7% complained of insomnia; 10% were lethargic or fatigued; 8.3% had headaches, and 7.3% had dizziness…Other CNS effects included nightmares, subjects feeling like they were stoned or had a hangover, and feelings of euphoria, dysphoria, confusion and trouble concentrating.”

“This is the first report of a patient developing CNS [Central Nervous System] vasculitis [blood vessel inflammation] after the initiation of HAART. The symptoms appeared and disappeared with the introduction and discontinuation of HAART.”

“We recently observed 2 patients who developed severe neuropsychiatric complications during treatment with abacavir. Thus far, there have been no reports of effects of abacavir on the central nervous system other than headache. The first patient was a 44-year-old white woman with human immunodeficiency virus (HIV) infection, and hepatitis B and C virus coinfection. During initial treatment with nelfinavir, stavudine, and lamivudine, the only side effect was diarrhea, for which nelfinavir was replaced by abacavir. Within days after switching drugs, she complained of night sweats and depression. Results of liver tests were abnormal, and all antiretroviral treatments were stopped. She felt much better, and her depression disappeared. Two months later, when the liver test results had normalized, the same treatment regimen that included abacavir was restarted. She became depressed and had suicidal thoughts and episodes of anxiety with difficulty in breathing. She became very emotional and complained of nightmares, muscle pain, headache, nausea, loss of appetite, and weakness…The second patient was a 37-year old white woman with coinfection of HIV and hepatitis C virus. She was initially treated with indinavir, lamivudine, didanosine, and zidovudine, and then ritonavir, saquinavir, and stavudine. She was later switched to zidovudine, lamivudine, and abacavir. From the start of this treatment, she had mood changes and became increasingly depressed with suicidal thoughts. A headache, which she had had for more than 1 year, progressed to severe migraine attacks with vomiting. Moreover, she complained of auditory hallucinations and anorexia…Several months later, her antiretroviral treatment was stopped, the migraine and psychiatric problems disappeared rapidly, and they did not reappear after starting nevirapine, zidovudine, and lamivudine. These two case reports strongly suggest that abacavir may have adverse effects on the central nervous system.”

“Peripheral neuropathy [damage to surface nerves, resulting in numbness or aching or burning pain] has emerged as the most common neurological complication of HIV infection…Some [cases] represent a consequence of HIV infection producing neuropathological damage…while others are related to opportunistic pathogens…An increasingly common group is that which occurs as a result of treatment toxicity (e.g., toxic neuropathy from antiretroviral drugs and lactic acidosis syndrome).”

“57% of our cases in this group had been prescribed HAART. In our study population, accessibility to the latest antiretroviral therapy was widespread…The incidence of HIV encephalopathy increased over time.”

“We report three cases of neuropsychiatric sequelae to nevirapine in patients with HIV infection but no history of mental illness…These three cases depict a delirium, an organic affective state, and an organic psychosis. The time the patients started nevirapine treatment was clearly related to the evidence of symptoms, and all cases resolved on withdrawal of nevirapine.”

“CNS [central nervous system] complications in patients with HIV, including psychiatric syndromes, delirium, seizures, and cognitive impairment, may in some cases reflect consequences of treatment with antiretroviral drugs that penetrate the CNS. For example, zidovudine and efavirenz, both considered attractive choices for patients with CNS complications because they have good CNS penetration, are themselves associated with potentially significant neuropsychiatric complications. In contrast, treatment with interferon, which has poor CNS penetration, is also associated with a high rate of CNS complications. Peripheral neurologic complications including neuropathic [surface nerve] pain [‘the pain…can be severe, irreversible, and debilitating’], neuropathic weakness, and denervation syndromes have been attributed to various toxic and metabolic factors in association with antiretroviral treatment.”

“we report the case of an HIV-infected individual who presented with VZV [Varicella Zoster Viral] meningitis and retrobulbar optic neuritis preceding the onset of progressive outer retinal necrosis, in which this latter complication was precipitated by the use of intravenous steroids…He had received multiple antiretroviral regimens, the last combination consisting of zidovudine, lamivudine, and efavirenz [was] discontinued 12 months prior to admission due to elevation of liver enzyme levels…The patient's headaches improved by day 5, but vision in his left eye became progressively worse to only light perception. On day 11 the ophthalmology service recommended intravenous steroids for the treatment of possible HIV optic neuropathy. Two days after the administration of steroids, his visual loss became more severe and at this point his retinal exam showed signs of progressive outer retinal necrosis [decay of the retina]. Intravenous foscarnet was started together with intraocular ganciclovir. One day after antiviral therapy was initiated the patient developed a vesicular rash compatible with either varicella or disseminated zoster. Despite antiviral treatment he had minimal recovery of his vision loss 3 months after treatment.”

“This study describes a form of severe, HIV-associated leukoencephalopathy in 7 patients who failed highly active antiretroviral therapy (HAART). Our observations are consistent with recent reports of an increased incidence of focal white matter lesions in HAART-treated patients and of an unexpectedly high incidence of ‘not determined’ leukoencephalopathy in AIDS patients. Prior to the HAART era, most reports described leukoencephalopathy cases that were either associated with opportunistic pathogens…or did not specifically exclude them…the leukoencephalopathy we describe is more severe than that described prior to the use of HAART…[In our patients] Leukoencephalopathy more probably resulted from HIV, the immune system, or antiretroviral drugs…The emergence of this condition in the post-HAART era strongly argues that potent ART [anti-retroviral therapy] plays an important role in pathogenesis.”

“We report three cases of neuropsychiatric sequelae [adverse effects] to nevirapine in patients with HIV infection but no history of mental illness...Within two weeks of starting nevirapine a 35 year old man developed low mood and had to stop working because of cognitive impairment and clouding of consciousness...Five days later, fearing that nursing staff would kill him, he leapt through a third floor window. As the temporal connection to his deterioration was unclear, nevirapine treatment was restarted. After a two week period of lucidity, he experienced a fluctuating course of impaired consciousness, lability of affect of treatment, and visual hallucinations. Nevirapine was withdrawn and within three weeks he was asymptomatic. In another case, a 36 year old woman experienced delusions of persecution and infestation within two weeks of starting nevirapine treatment. Command hallucinations led to an impulsive suicide attempt. In a third case, a 42 year old woman developed persecutory delusions and depressive thoughts 10 days after starting nevirapine. Treatment with antipsychotic drugs was stopped in both of these cases after several weeks (risperidone, four weeks, and olanzapine, three weeks, respectively). Both patients remained asymptomatic, indicating that a degenerative process was not involved...The time the patients started nevirapine treatment was clearly related to the evidence of symptoms, and all cases resolved on withdrawal of nevirapine.”

“The use of efavirenz [sustiva], a non-nucleoside reverse transcriptase inhibitor [NNRTI], may be limited by psychiatric symptoms that require treatment discontinuation...We report here three informative cases of patients who presented with sudden and severe neuropsychiatric symptoms during therapy with efavirenz”

“Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy [muscle damage] or neuropathy [nerve damage] after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamivudine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis [dangerously high levels of lactic acid in the blood]…The myopathy is characterized by muscle wasting, myalgia [muscle pain], fatigue, weakness and elevation of CK [creatine kinase, an enzyme that turns creatine into phosphocreatine]. The neuropathy is painful, sensory and axonal.”

“Central nervous system symptoms reported in all treatment groups included, but were not limited to, dizziness, impaired concentration, insomnia, and abnormal dreaming. The incidence was 58 percent in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors, 53 percent in the group given efavirenz plus indinavir, and 26 percent in the group given indinavir plus nucleoside reverse-transcriptase inhibitors”

“[Neurological adverse events reported in Table 3 from a 12 week study period in the two groups taking only 1200 mg or 1800 mg Abacavir daily (and no other antiretroviral drugs) included: Headache (70% for the 1200mg group and 70% for the 1800 mg group); Asthenia (general weakness; 25%/30%); Insomnia (30%/5%); Dizziness (20%/30%))]”

“All patients treated with high-dose ddC [2’,3’-dideoxyciytidine] (0.06 and 0.03 mg/kg every 4 hours) developed a painful, predominantly sensory peripheral neuropathy [burning or shooting pain followed by weakness and numbness], with a mean onset of 7.7 weeks, which reached severe intensity over several days...Treatment with 0.01 mg/kg every 4 hours produced a similar neuropathy, although of milder severity, later onset (mean, 9.3 weeks), and slower progression...Only 2 of 6 patients treated with 0.005 mg/kg every 4 hours developed clinical or laboratory evidence of neuropathy”

“A reversible, toxic neuropathy was observed in 10 or 44 (23%) of patients enrolled in a phase I trial of ddI [4 other patients symptoms that did not meet the definition of neuropathy]. These patients were taking higher daily doses of ddI and tended to have higher cumulative doses of ddI than did the patients who did not develop neuropathy. ..Extended follow-up of the patients who developed a peripheral neuropathy indicated that most of the neuropathic symptoms were reversible with discontinuation or dose reduction of ddI. However, there often was a brief period of continued exacerbation before the improvement occurred. Our results indicate that it may take several months for the symptoms to resolve.”

“During the study period, 64 patients were referred to the HIV neurology clinic and evaluated by one of the authors. The most common reason for referral was evaluation of peripheral neuropathy [20/64], focal brain lesion [10], myopathy [4], myelopathy [3], and back pain [3]. 49 (77%) had serum vitamin B12 determinations obtained…10 of 49 patients who were tested were found to have abnormal vitamin B12 metabolism…The majority of patients had a macrocytic anemia (70%); however, all of these patients were also receiving zidovudine [no word on how many of the other three were taking AZT]”