Neurological Manifestations of HIV

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FIGURE. Neuropathic versus nociceptive pain

TABLE. Interactions between opiates and ART

Dr Faktorovich is Assistant Professor of Neurology (pending), Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Dr Simpson is Professor of Neurology, Icahn School of Medicine, Mt Sinai, New York, NY.

Human immunodeficiency virus (HIV) is responsible for a wide spectrum of neurologic manifestations, with etiologies ranging from inflammatory, infectious, neoplastic. and more. The development of antiretroviral therapy (ART) has dramatically increased life expectancy, however neurologic complications remain a significant cause of long-term disability. Understanding and recognizing these conditions is crucial in effectively managing HIV patients.

Peripheral neuropathy

Peripheral neuropathy is the most common neurological complication in HIV/AIDS, it affects between 30% to 60% of individuals. It can be related to the virus itself, ART neurotoxicity, and other comorbidities. Distal sensory polyneuropathy (HIV-DSP) is the most common type of peripheral neuropathy, typically presenting with ascending numbness, paresthesia, and burning-type pain that occurs in a “stocking-glove” distribution.

Neurological evaluation reveals depressed ankle reflexes, increased vibratory threshold, and decreased sensation to pain and temperature. Proprioceptive loss, muscle weakness, and atrophy can be seen late in the disease course. Electrodiagnostic testing demonstrates a symmetrical, sensorimotor axonal neuropathy. Skin biopsy may also be useful, given the loss of epidermal nerve fibers which has been shown to correlate with clinical severity of DSP.¹

In the pre-ART era, HIV-DSP was associated with high viral load and low CD4 count. However, since the development of ART, this association has not been clearly demonstrated. Furthermore, some anti-retroviral agents, specifically dideoxy-nucleoside reverse transcriptase inhibitors have neurotoxic effects on peripheral nerve. Although the presentation can be similar, drug-related peripheral neuropathy is typically rapidly progressive, often within weeks of initiating an offending agent. Recognition is important, as the neuropathy typically improves with discontinuing the agent.

Inflammatory demyelinating polyneuropathy

HIV-related, inflammatory demyelinating polyneuropathy can occur at any point in the disease course, presenting in the acute or chronic form, similar to non-HIV related inflammatory demyelinating polyneuropathy. Acute inflammatory demyelinating polyneuropathy typically occurs as a monophasic illness, with symptoms peaking around 2 weeks followed by variable recovery time. It is more commonly seen with CD4 count of greater than 200 cells/mm3 (eg, during seroconversion).² Chronic inflammatory demyelinating polyneuropathy progresses over 8 weeks or more. Clinical presentation usually involves progressive, ascending weakness that starts in the legs. Pain accompanies the condition in more than 80% of cases, described as dysesthesias and/or deep, aching pain in the legs or lower back.³ Symptoms are notable for areflexia, ascending weakness, and relative sparing of sensation although some sensory impairment can occur. As in HIV negative individuals, these conditions are thought to be immune-mediated. In advanced AIDS, additional studies (ie, viral testing and nerve biopsy) may be necessary to rule out primary cytomegalovirus (CMV) infection of the peripheral nerve.

Electrodiagnostic testing typically reveals a primarily demyelinating, sensorimotor neuropathy, although secondary axonal loss may occur, especially in chronic inflammatory demyelinating polyneuropathy. Unlike seronegative patients where high protein without pleocytosis in the cerebral spinal fluid is a classic finding; cerebrospinal fluid testing is less reliable in the HIV population. HIV patients can have mild lymphocytic pleocytosis. MRI studies are usually normal, however may reveal evidence of nerve root enhancement.

Treatment of these conditions relies on immunomodulatory therapies such as intravenous immunoglobulin, plasmapheresis, and with caution, steroids, as well as neuropathic pain medications as needed.

Other neuropathies

Progressive polyradiculopathy is a rare, rapidly progressive condition that may resemble cauda equina syndrome. It can be seen in advanced HIV/AIDS, often associated with CMV infection. MRI is crucial to rule out a lesion compressing the cauda equina as well as to evaluate for the presence of lumbosacral nerve root enhancement. Cerebrospinal fluid testing most commonly reveals lymphocytic pleocytosis and positive CMV polymerase chain reaction. Early diagnosis and anti-viral treatment is crucial in preventing root necrosis and irreversible damage.

Mononeuritis multiplex presents as asymmetric, multifocal peripheral neuropathies affecting both motor and sensory modalities. Deep, aching pain or allodynia in affected regions is commonly described. Early on in the course of HIV, mononeuritis multiplex is typically an immune-mediated, self-limiting process. Opportunistic infections including CMV can be the cause in advanced HIV/AIDS and have a worse prognosis. Vasculitis is another possibility, which can be associated with HIV or coinfection with hepatitis C.

Myopathies

HIV infection is associated with a number of myopathies, although the mechanism by which HIV leads to muscle inflammation is not well understood. HIV-associated myopathy is the most common myopathy in these patients, typically presenting with a slowly progressive, symmetrical muscle pain and weakness affecting primarily proximal muscles. Laboratory results include elevated CK level, electrodiagnostic evidence of irritative myopathy and muscle biopsy revealing myofiber degeneration, often associated with inflammatory infiltrates. Although treatment guidelines have not been well established, immunomodulatory therapies including corticosteroids and IVIG have been successfully used.⁴ A similar condition, has been described in the setting of immune reconstitution inflammatory syndrome.

Additional inflammatory myopathies including dermatomyositis and inclusion body myositis has also been described.4 Furthermore, myopathy can be a rare adverse effect of zidovudine therapy. Infectious myopathies due to opportunistic infections such as Staphylococcus aureus can also occur.

Treatment of neuropathic pain

Pain, estimated to affect between 20% to 90% of HIV-infected individuals, is one of the most significant causes of disability in the HIV/AIDS population.^5-7 Categorizing pain into two categories, nociceptive and neuropathic, is helpful in determining the appropriate treatment plan (Figure). Neuropathic pain results from abnormal neural transmission following an initial injury to the peripheral or CNS, which persists even in the absence of additional damaging stimuli. Aberrant reorganization of neural tissues after the initial injury can result in ongoing, abnormal signaling and chronic, neuropathic pain.

Pharmacologic therapy is the mainstay of treating neuropathic pain. Because of the lack of HIV-specific guidelines, current recommendations are based on those for other forms of peripheral neuropathy including diabetic neuropathy and post-herpetic neuralgia.

Multiple categories of drugs have long been used in the treatment of neuropathic pain. Among antidepressants, tricyclic antidepressants including amitriptyline and nortriptyline have demonstrated efficacy in diabetic neuropathy, post-herpetic neuralgia as well as primary headaches, low back pain, and fibromyalgia. However, these agents failed to show benefit in HIV-related neuropathy.^8,9 Of note, protease inhibitors may increase TCA serum levels, increasing the risk of toxic adverse effects.¹⁰

Several SNRIs including duloxetine and venlafaxine have shown benefit in the treatment of diabetic polyneuropathy and migraines, with fewer adverse effects than amitriptyline.^11-13 These agents have unfortunately not been studied in HIV-related polyneuropathy. SSRIs have not shown any analgesic benefit.

Anticonvulsant therapy such as gabapentinoids (gabapentin and pregabalin) are widely used neuropathic agents. One small study on HIV-DSP demonstrated significant pain reduction and improved sleep with the use of gabapentin.¹⁴ Pregabalin, however failed to show a benefit when compared to placebo in two large multicenter trials, predominantly due to the high placebo response.^15,16 Lamotrigine, another anticonvulsant, has shown benefit in conditions including trigeminal neuralgia, diabetic polyneuropathy, and complex-regional pain syndrome.17 However because of its complex titration schedule and concern of potentially serious adverse effects including Steven Johnson syndrome, it is not commonly used in neuropathic pain.

Opiate use in non-cancer related pain has been a controversial issue because of the risk of serious adverse effects and dependency. However in severe, refractory pain, opiates may be an effective treatment both in neuropathic and nociceptive pain. Precautionary measures should include starting with immediate release formulations at the lowest effective dose, regularly assessing the risks and benefit, and discontinuing therapy once the risks outweigh the benefits. Many opiates have interactions with anti-retroviral agents, which should be considered when planning a treatment regimen (Table).

Another agent, high dose topical capsaicin, derived from chili peppers, has demonstrated significant pain reduction in HIV neuropathy up to 12 weeks post application.^18,19 However, treatment availability and pain with application has limited its use. Cannabinoids have also emerged as a potential therapy for chronic neuropathic pain, with several studies that demonstrated pain reduction in HIV-DSP.^20,21

Given the complexity of treating HIV-related neuropathic pain and limited evidence for most of the agents, combination therapy using agents with different mechanisms of action is often used. Furthermore, non-pharmacologic therapies, such as physical activity, cognitive behavioral therapy, and acupuncture should also be considered.

HIV-associated neurocognitive disorder

HIV-associated neurocognitive disorder (HAND) has historically been a significant cause of disability in HIV, estimated to affect up to 50% of patients.²² Presentation is often insidious. Common symptoms include cognitive slowing, impaired concentration and memory, and behavioral changes. Motor disturbances such as psychomotor slowing, gait impairment, clumsiness, and even movement disorders (eg, parkinsonian features, chorea) have also been described.

In mild cases, bedside neurological exam may be normal. Cortical findings such as aphasia is less commonly seen, suggesting predominantly subcortical involvement. MRI studies typically reveal cerebral atrophy, especially in the hippocampus and basal ganglia, often with associated bilateral and symmetrical white matter abnormalities.

Although good viral control is protective against the development of HAND early on, this condition appears to re-emerge late in the disease course in older populations. Risk factors include advanced age, low CD4 count, longer duration of HIV illness, AIDS-defining illnesses and high viral load. Medical and lifestyle (such as substance abuse) comorbidities also likely play a role.

The pathophysiology of HAND is not well understood although it is possibly multifactorial. A few contributors likely include direct cerebral toxicity from the HIV virus, chronic inflammation in the setting of HIV, elaboration of HIV-associated neurotoxins, and associated metabolic changes that increase the risk of cerebrovascular disease and amyloidosis.

Headache syndrome

Primary headache. Headaches may occur in up to 60% of HIV-infected individuals and have a wide range of potential etiologies.23 Migraine and tension-type headaches are most common.²⁴ Lower CD4 count is associated with higher frequency and severity of these conditions.²³

Migraines are treated similarly in HIV as in the general population, with a few exceptions. For example, ergots (such as dihydroergotamine) are contraindicated in patients taking protease inhibitors and non-nucleoside reverse transcriptase inhibitors because of the risk of psychosis, seizures, and gangrene, and therefore are not typically used in the HIV population. Steroids, which are occasionally used for abortive therapy, should be used with caution because of the risk of additional immunosuppression.

Secondary headaches. CNS manifestations of HIV can occur at any point in the disease progression because of the high viral permeability through the blood–brain barrier. A dull, bilateral headache can occur in patients during the prodromal stage, 2 to 4 weeks after exposure. Aseptic meningitis, manifesting with fever, meningismus, and cranial neuropathies, can also occur at any point in the disease course and are typically self-limited.

Opportunistic infections must always be considered when assessing new-onset headaches in an HIV patient and therefore warrants careful evaluation, especially in those with low CD4 count. Toxoplasmosis and progressive multifocal leukoencephalopathy are the most common focal, CNS infections associated with HIV.²⁵

Toxoplasmosis, a parasitic infection caused by Toxoplasma gondii, can present as focal granulomas, abscesses or leptomeningitis especially in patients with a CD4 count of less than 100. Progressive multifocal leukoencephalopathy, caused by the John Cunningham (JC) virus, consists of patchy or confluent lesions within the white matter. Focal neurologic deficits are commonly seen in these conditions although indolent headaches can also be the primary presenting feature. Cryptococcus is another frequently seen agent, often presenting with indolent headache and confusion with or without overt signs of meningismus. CMV, seen in advanced AIDS (CD4 <50), typically causes diffuse meningoencephalitis.

Opportunistic intracranial malignancies are also potential causes of headaches and focal neurological symptoms. Primary CNS lymphoma is the most common, although systemic lymphoma with CNS metastases and intracranial Kaposi sarcoma can also occur.

Treatment of secondary headaches is centered on treating the underlying condition. However many of the abortive therapies used in treatment of primary headaches may also be used for severe or refractory pain. Opiates, which are not recommended in primary headaches, can be used with caution for severe pain in those with secondary headaches.

This article was originally published on 8/17/18 and has since been updated.

References:

1. Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology. 2007;68:2113-2119.

2. Lyons J, Venna N, Cho TA. Atypical nervous system manifestations of HIV. Semin Neurol. 2011;31:254-265.

3. Moulin DE, Hagen N, Feasby TE, et al. Pain in Guillain-Barré syndrome. Neurology. 1997;48:328-331.

4. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009;40:1043-1053.

5. Douaihy AB, Stowell KR, Kohnen S, et al. Psychiatric aspects of comorbid HIV/AIDS and pain: part 1. AIDS Read. 2007;17:310-314.

6. Frich LM, Borgbjerg FM. Pain and pain treatment in AIDS patients: a longitudinal study. J Pain Symptom Man. 2000;19:339-347.

7. Kirsh KL, Whitcomb LA, Donaghy K, Passik SD. Abuse and addiction issues in medically ill patients with pain: attempts at clarification of terms and empirical study. Clin J Pain. 2002;18(4 Suppl):S52-60.

8. Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection: AIDS Clinical Trial Group 242 Protocol Team. Neurology. 1998;51:1682-1688.

9. Shlay JC, Chaloner K, Max MB, et al. Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA. 1998;280:1590-1595.

10. Krashin DL, Merrill JO, Trescot AM. Opioids in the management of HIV-related pain. Pain Phys. 2012;15(3 Suppl):ES157-168.

11. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;1:CD007115.

12. Aiyer R, Barkin RL, Bhatia A. Treatment of neuropathic pain with venlafaxine: a systematic review. Pain Med. 2016;18:1999-2012.

13. Ozyalcin SN, Talu GK, Kiziltan E, et al. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45:144-152.

14. Hahn K, Arendt G, Braun JS, et al. A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J Neurol. 2004;251:1260-1266.

17. McCleane GJ. Lamotrigine in the management of neuropathic pain: a review of the literature. Clin J Pain. 2000;16:321-326.

18. Simpson DM, Brown S, Tobias J, Group, N-CS. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology. 2008;70: 2305-2313.

19. Brown S, Simpson DM, Moyle G, et al. NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials. AIDS Res Ther. 2013;10:5.

20. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacol. 2009;34: 672-680.

21. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515-521.

22. Smail RC, Brew BJ. HIV- associated neurocognitive disorder. Handbk Clin Neurol. 2018;152:75-97.

23. Kirkland KE, Kirkland K, Many WJ, Smitherman TA. Headache among patients with HIV disease: prevalence, characteristics, and associations. Headache. 2012;52:455-466.

24. Evers S, Wibbeke B, Reichelt D, et al. The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses. Pain. 2000;85:191-200.

25. Brew B., Miller J. Human immunodeficiency virus-related headache. Neurology. 1993;43:1098-1100. ❒