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HIV NEUROLOGY.pptx
- 1. HIV NEUROLOGY BY: Dr. REBIL HEIRU (IMR3) MODERATOR: DR. HANNA (CONSULTANT NEUROLOGIST) NOVEMBER, 2021 G.C ADDIS ABABA, ETHIOPIA
- 2. OUTLINE • Spinal cord diseases • Peripheral nervous System diseases • Myopathy • ART associated neurologic complications • Reference
- 3. Spinal cord disease • Spinal cord disease, or myelopathy, is present in ~20% of patients with AIDS • 90% of the patients with HIV-associated myelopathy have some evidence of dementia • Two main types of spinal cord disease are seen in patients with AIDS. vacuolar myelopathy Spinal dorsal sensory tractopathy
- 4. HIV-ASSOCIATED VACUOLAR MYELOPATHY • Most often seen in advanced AIDS, and concurrent HIV-associated dementia and DSP is common • Rare since the advent of ART • Apparent pathologically in 25% to 55% of AIDS autopsy series • Patients develop • slowly progressive spastic paraparesis with associated gait disturbance, • impaired bladder control, and • sensory dysfunction • Examination demonstrates weakness and impaired vibratory and proprioceptive sense with myelopathic signs including brisk DTR and lower extremity spasticity
- 5. • MRI of the spinal cord • atrophy and T2 hyperintensities in the posterior and lateral columns diffusely • although this is usually most severe in the mid lower thoracic spinal cord • Pathologically • vacuolation of the white matter is seen, as suggested by the name • Other causes of myelopathy to consider in patients with HIV include: • Metabolic etiologies (eg, vitamin B12 or copper deficiency) and • Infections including syphilis, CMV, varicella-zoster virus (VZV),
- 6. • Compared with VM, these disorders • may progress more rapidly • often with associated back or radicular pain and • the presence of a discrete sensory level over the trunk IX: Spinal MRI, which may reveal cord swelling with intramedullary enhancement and T2 signal changes, and CSF PCR testing for viral DNA.
- 7. • As with HIV-associated dementia, ART is the mainstay of therapy (limited benefit) + supportive Rx. • Patients with myelopathy and paraplegia require considerable assistance, comparable to that of other spinal cord–injured patients. • Individualized attention for • Care of the neurogenic bladder • bladder infection • management of limb spasticity • prevention of skin breakdown and decubiti, and assist devices to improve mobility are the issues that require individualized attention.
- 9. HIV-ASSOCIATED PERIPHERAL NEUROPATHY • Peripheral neuropathies are common in HIV infection and they occur at all stages of illness and take a variety of forms. • Although symptomatic neuropathy occurs in approximately 10% to 25% of HIV-infected patients overall • Pathological evidence of peripheral nerve involvement is present in virtually all end- stage AIDS patients. • There are five major clinical types of HIV-associated neuropathies: 1. DSPN 2. Acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP) 3. CMV-associated polyradiculomyelopathy 4. Drugs-associated toxic neuropathies 5. Vasculitic neuropathy
- 10. Distal Sensory Polyneuropathy (DSP) • Also called HIV-associated neuropathy or AIDS neuropathy • The most common peripheral nerve syndrome that complicate HIV infection …affects 30% to 50% of individuals who are HIV infected • The 1-year incidence of DSP showed a steep decline in the post-cART compared with the pre-cART period. • However, just like milder forms of HAND, the overall prevalence of DSP appears to be increasing as HIV-infected persons live longer with the disease • Axonal polyneuropathy, predominantly sensory and length-dependent • More common in taller and older individuals with lower CD4 counts; tobacco use also increase the risk
- 11. • Risk factors: • Advanced immunosuppression CD4 113/microL (26-275 cells/microL) • High viral load (HIV RNA level >10,000 copies/ml) 2-3X • Advanced age • Longer duration of HIV infection • Host factors (DM, hypertriglyceridemia, nut. deficiencies, mitochondrial polymorphism) • Substance Use and Neurotoxic drugs • Alcohol
- 12. • common clinical manifestations • slowly progressive and mild numbness, tingling, and paresthesia in a stocking-glove distribution in the feet • depressed or absent ankle jerks • Pain, temperature and vibratory sensory loss • severe burning pain and paresthesia develop less frequently • Symmetrical involvement is a characteristic clinical feature • The hands are usually spared until the disorder is advanced • Typically spares motor function and proprioception • but walking may be impaired because of severe pain
- 13. • The pathogenesis of DSPN is not well understood • Proposed mechanisms include toxicity to the dorsal root ganglion • from cytokine up-regulation • HIV antigens and • the effects of chronic multisystemic illnesses • Electromyography and nerve conduction studies… not usually needed • Nerve conduction studies demonstrate reduced or absent sensory nerve action potentials (SNAPs) consistent with axonal polyneuropathy, and • Needle EMG may demonstrate partial denervation of distal leg muscles.
- 14. • Exposures to neurotoxins?, including ethanol • Neurotoxic drugs • the nucleoside analogs, didanosine, zalcitabine, and stavudine • isoniazid, pyridoxine, dapsone, metronidazole, and vincristine. • Screening for vitamin B12 deficiency and diabetes mellitus
- 15. • Treatment goals in DSPN • minimizing neurotoxic exposures • virus suppression by HAART and • management of pain. • Medications for symptomatic management of neuropathic pain include antidepressants and antiepileptic drugs, as well as topical analgesics. • Gabapentin, amitriptyline, pregabalin, nortriptylin, duloxetine, capsicin, medical cannabinoids, acupuncture • Other treatments: Treatment-naïve patients may respond to ART.
- 16. Nucleoside Analog - Associated Toxic Neuropathy • A painful polyneuropathy that closely resembles DSPN … mitochondrial toxicity is postulated to be the underlying mechanism • The nucleoside analog ARV agents, didanosine, zalcitabine, and stavudine • Nucleoside neuropathy Vs DSPN. • First nucleoside neuropathy typically evolves over weeks following initiation of therapy…in contrast DSPN progresses over months or even years. • Second, stopping the offending agent eventually leads to stabilization and regression of nucleoside neuropathy over several months • “coasting” • Treatment similar to DSPN
- 17. Inflammatory Demyelinating Polyradiculoneuropathies (AIDP and CIDP) • Less common than the painful neuropathies related to HIV or nucleoside antiretrovirals • often develop during early HIV infection, sometimes around the time of seroconversion • AIDP, or the Guillain-Barré syndrome typically presents as • rapidly progressive ascending weakness with areflexia, variably accompanied by respiratory failure and dysautonomia • The Miller-Fisher variant has also been described
- 18. • In CIDP neuropathic weakness and sensory loss occur in a more indolent or episodic manner • Patients who are HIV positive with CIDP are more likely to be • younger and female • have a monophasic course, and respond to steroids than individuals who are not HIV infected with CIDP • In both AIDP and CIDP, electrophysiological studies reveal • slowed conduction, temporal dispersion, multifocal block, and prolonged F waves indicating demyelination • The CSF often shows a lymphocytic pleocytosis (10 to 50 cells/mL) and elevated protein • Treatment: IVIG, plasmapheresis and corticosteroids (only in CIDP)
- 19. Lumbosacral Polyradiculomyelitis • Subacute lumbosacral polyradiculomyelitis with variable cord involvement • Uncommon syndrome that results from a variety of infectious agents most notably CMV C/F : • A rapidly developing cauda equina syndrome with leg weakness • later sphincter dysfunction, sacral and leg paresthesias and sensory loss, and areflexia • typically evolve over several days
- 20. • If it develops in a patient with • CD4+ count less than 50/µL • CSF reveals marked polymorphonuclear pleocytosis • elevated protein, and low to normal glucose levels • CMV infection of the nerve roots with subsequent inflammation and necrosis of the roots is the likely cause. • CMV PCR or branched DNA assay in CSF is a helpful confirmatory test • Treatment • Intravenous ganciclovir • Foscarnet, either alone or with cidofovir
- 21. Other Neuropathies and Neuronopathies Mononeuritis multiplex (MM) • A relatively rare peripheral nerve syndrome of HIV infection • Multifocal asymmetrical peripheral nerve lesions that may include cranial nerves. • ?Vasculitic phenomenon • When it develops in early or midstage HIV infection…corticosteroid therapy • May be self-limited • MM complicating advanced HIV infection, with CD4+ count less than 50/mL, may be caused by CMV and responds to intravenous ganciclovir
- 22. Amyotrophic lateral sclerosis (ALS) • An ALS-mimicking syndrome has been reported in HIV disease • Improves or resolves completely with initiation of ART • Occurs at younger ages compared to individuals with ALS who are not HIV infected
- 23. • Myasthenia gravis (MG) • has been described in association with HIV (uncommon in HIV) • Majority of cases associated with Ach receptor Abs and a few associated with muscle-specific kinase (MuSK) antibodies. • Treatment is similar to HIV neg patients • The added nuance that monitoring is needed b/c worsening of MG symptoms may be seen in the first 6 months of initiating ART. • Potential drug interactions, as well as potential reactivation of latent viral infections
- 24. Myopathies • May be a consequence of HIV it self, ART drugs or both • Secondary myopathies may a occur, but less common In HIV infected individuals • Myopathic symptoms in HIV-infected individuals can arise from • Toxic (zidovudine) or • Dysimmune (polymyositis) causes or from • AIDS cachexia (muscle wasting syndrome) • HIV associated myopathy (polymyositis) • ART associated • Zidovudine associated myopathy • HIV associated neuromuscular weakness syndrome (HANWS)
- 25. HIV associated polymyositis • Subacute progressive Proximal weakness and, less commonly, myalgia due to a polyclonal hyperimmune response following HIV infection • May occur with immune restoration following HAART • Develop at any time during HIV infection • P/E: Symmetrical weakness (neck flexors and upper limb and lower limb proximal muscles) • DTR are preserved …unless super imposed Peripheral neuropathy
- 26. • An important laboratory test for myopathy is serum creatine kinase (CK) leve • which can be elevated roughly 2–4 times the normal values…92% of patients with myopathy had CK elevations. • The degree of CK elevation is highly variable, sometimes elevated to >1000 IU/L. • The CK level correlates with the degree of myonecrosis seen in muscle biopsy, but does not correlate well with the degree of muscle weakness • Pronounced elevations in CK may occur in asymptomatic patients, particularly after exercise.
- 27. • Electromyography (EMG) is a sensitive diagnostic test for HIV associated myopathies • with up to 94% diagnostic yield in one series of 50 patients with HIV associated myopathy • Electrophysiological studies often reveal • myopathic motor units and • increased insertional activity and spontaneous activity typical of an inflammatory myopathy. • Frequently, abnormal irritative activity, such as fibrillation potentials, positive sharp waves and complex repetitive discharges, is found. • The iliopsoas is the most sensitive muscle for EMG diagnosis
- 28. • Muscle biopsy reveals fiber-size variability, fiber degeneration, and endomysial infiltrates • Cytoplasmic bodies and nemaline rod bodies are other common histological features • HIV does not appear to directly infect muscle fibers, but rather induces them to express major histocompatibility complex I, triggering cell-mediated muscle fiber injury • Treatment: immunomodulatory medications (steroids, IVIg or plasma exchange)
- 29. Zidovudine Myopathy • A toxic mitochondrial disorder which presents with the insidious onset of proximal weakness and myalgia • Difficult to distinguish clinically from HIV-associated myopathy • Typically after taking zidovudine for at least 6 months • Serum CK may be normal or elevated • Muscle biopsy shows histological features suggesting mitochondrial dysfunction with no or scanty inflammation • RRF are a histologic hallmark of zidovudine-induced myopathy • Clinical response to a drug holiday or reduction in zidovudine dose often obviates the need for muscle biopsy
- 30. Neurologic complication of ART
- 32. Reference • Bradley's Neurology in Clinical practice, 8th edition • Harrison 20th edition • CONTINUUM: Neurologic Complications of Human Immunodeficiency Virus Infection • Uptodate 2018
- 33. Thankyou!
Editor's Notes
- The second form of spinal cord disease involves the dorsal columns and presents as a pure sensory ataxia. The third form is also sensory in nature and presents with paresthesias and dysesthesias of the lower extremities. In contrast to the cognitive problems seen in patients with HIV encephalopathy, these spinal cord syndromes do not respond well to antiretroviral drugs, and therapy is mainly supportive
- Causes the protective myelin sheath to pull away from nerve cells of the spinal cord, forming small holes (vacuoles) in nerve fibers
- Pathologically, vacuolation of the white matter is seen, as suggested by the name, and in autopsy studies this entity appeared to be more widespread than is clinically recognized The pathogenesis of vacuolar myelopathy is unknown, but may be related to abnormal transmethylation mechanisms induced by the virus and/or cytokines. In one series of 16 patients, there was no correlation between the viral load in the CSF and the presence or severity of myelopathy [56]. Pathological descriptions include demyelination of the dorsal columns and the dorsal half of the lateral columns, with prominent vacuoles within the myelin sheaths. This pathologic appearance is similar to the changes seen in the subacute combined degeneration of the cord Numerous other infectious, neoplastic, and metabolic disorders occasionally cause myelopathy in patients with HIV infection, and they need to be differentiated from VM. Compared with VM, these disorders may progress more rapidly, often with associated back or radicular pain and the presence of a discrete sensory level over the trunk. CMV, VZV, herpes simplex virus type-2, and other pathogens may cause myelitis. Helpful diagnostic tests include spinal MRI, which may reveal cord swelling with intramedullary enhancement and T2 signal changes, and CSF PCR testing for viral DNA. Because HIV shares risk factors with human T cell lymphotropic virus I and II, co-infection with these retroviruses also may cause myelopathy in the HIV-infected patient.
- Although there is limited benefit in slowing progression once this condition has developed, cases of improvement have been reported. Care of the neurogenic bladder, bladder infection, management of limb spasticity, prevention of skin breakdown and decubiti, and assist devices to improve mobility are the issues that require individualized attention.
- The most commonly encountered neurologic complication of HIV is distal symmetric polyneuropathy. Although ART has both decreased the incidence of neuropathy and slowed disease progression in patients with distal symmetric polyneuropathy, asymptomatic peripheral neuropathy (as defined by mild impairment in vibratory sensation in the great toes or diminished ankle reflexes bilaterally on examination in the absence of clinical symptoms) may be present despite virologic control. Older age, history of impaired glucose tolerance, and neurotoxic ART use (specifically protease inhibitors) have been found to be associated with an increased risk of symptomatic peripheral neuropathy in patients infected with HIV, but the mechanisms of pathogenesis are varied. Macrophage activation has been identified in the epineurium in association with axonal degeneration and nerve fiber loss on nerve biopsy examinations, suggesting an immune-mediated mechanism, although the precise pathogenesis of HIV-associated distal symmetric polyneuropathy is unclear. Peripheral neuropathy has also been associated with the presence of elevated CSF inflammatory markers (neopterin and monocyte chemotactic protein-1 levels) in primary HIV infection (less than 1 year after HIV transmission). This may reflect the correlation between immune activation in both CNS and peripheral nervous system (PNS) compartments as a result of synchronous infection, although it is also possible that proinflammatory molecules released from peripheral nerves may induce CNS changes by altering cell trafficking.
- Risk factors — In the era prior to potent antiretroviral therapy (ART), DSPN usually occurred in the setting of advanced immunosuppression In one report, for example, the mean CD4 count was 113/microL (range 26 to 275 cells/microL) In addition to immunosuppression, the level of HIV viremia was also correlated with the development of DSPN and the severity of symptoms In the Multicenter AIDS Cohort Study, the risk of DSPN was increased 2.3-fold in patients with an HIV RNA level >10,000 copies/mL at baseline [14]. However, in the era of potent ART, immunosuppression or high levels of viremia have not been associated with the development of DSPN in the vast majority of There are conflicting data on whether coinfection with hepatitis C is associated with DSPN [6,20,21]. Other factors associated with DSPN include aging, longer duration of HIV infection, host factors such as diabetes, hypertriglyceridemia, nutritional deficiencies, mitochondrial polymorphisms, substance use and the use of older nucleoside reverse transcriptase inhibitors such as didanosine and stavudine In a large prospective study, 2141 HIV-infected patients were followed longitudinally for seven years with annual screening for symptoms and signs of peripheral neuropathy [27]. The risk of peripheral neuropathy was associated with aging and nucleoside analog use while sensory loss was associated with older age, nucleoside analog use, and diabetes. In ART-experienced patients, female sex, taller height, alcohol consumption, higher plasma creatinine, smoking, and use of isoniazid have been identified as additional risk factors for peripheral neuropathy [21,29]. Effect of antiretroviral therapy on prevalence — In most studies, the incidence of HIV-associated DSPN appears to have decreased in the era of potent ART compared with earlier cohorts, suggesting that effective suppression of HIV itself may have a beneficial effect on peripheral nerve function (figure 1) [5,7,15,16,30]. As an example, in a large cohort of 2515 HIV-infected patients, certain drugs (didanosine, stavudine, nevirapine, and certain protease inhibitors) were associated with the development of DSPN in the first year of use [5]. However, patients who did not develop DSPN in the first year of ART had a decreased risk of developing this complication with continued drug exposure. In another cohort of 2165 patients followed for more than 3 years, incidence rates of peripheral neuropathy also declined with the initiation of ART [31]. These data suggest that immune restoration, or viral suppression of HIV, lead to a decreased risk of DSPN [5].
- Distal symmetric polyneuropathy is typically sensory predominant with mixed small and large fiber involvement, causing pain, paresthesia, and hypersensitivity in the feet . Examination demonstrates alterations in pain and temperature sensation, reduced vibratory sensation to a lesser degree, diminished or absent Achilles deep tendon reflexes, and a normal motor examination. Nerve conduction studies demonstrate reduced or absent sensory nerve action potentials (SNAPs) consistent with axonal polyneuropathy, and needle EMG may demonstrate partial denervation of distal leg muscles. The differential diagnosis includes ART toxicity (specifically the use of antiretroviral nucleoside reverse transcription inhibitors including didanosine and stavudine) and other causes of peripheral neuropathy seen in patients not infected with HIV, such as vitamin B12 deficiency, impaired glucose tolerance, and toxins such as alcohol.
- Treatment of distal symmetric polyneuropathy comprises ART to achieve virological suppression as previous studies have demonstrated plasma HIV-1 RNA levels are associated with increased severity of neuropathy. Medications for symptomatic management of neuropathic pain include antidepressants and antiepileptic drugs, as well as topical analgesics. Treatment rationale is based on extrapolation of data for use of such agents for diabetic and postherpetic neuropathy because data are limited and conflicting for use specifically in HIV-associated neuropathic pain for agents such as lamotrigine, amitriptyline, lidocaine gel, and topical capsaicin cream. When selecting therapy, specific attention should be given to avoidance of interactions with ART medications.
- Mononeuritis multiplex is characterized by sequential multifocal, noncontiguous typically painful sensory and motor nerve dysfunction May occur in the setting of HIV as a vasculitic phenomenon as supported by the presence of perivascular inflammation and epineural microvascular necrosis. Although initially patchy and asymmetric, this may evolve to mimic a distal symmetric peripheral neuropathy pattern. Reduced evoked sensory and compound motor action potentials (CMAPs) on nerve conduction studies and EMG support this diagnosis. Corticosteroids and/or IVIg is used for treatment. The main differential diagnosis in patients infected with HIV is CMV radiculitis, which most commonly occurs when the CD4+ count is less than 50 cells/mm3.
- although numerous cases have been reported in the literature and include patients with MG before HIV infection, those who developed MG after HIV infection (most of whom had normal CD4+ counts), and several rare cases of simultaneous diagnoses of both HIV and MG. In addition, one should remain mindful of potential drug interactions, as well as potential reactivation of latent viral infections (in a case review of 16 patients treated for HIV and MG, none developed an opportunistic infection, and one had reactivation of varicella-zoster rash).
- In a retrospective series by Simpson et al. (1993), 92% of patients with myopathy had CK elevations.
- EMG reveals a typical myopathic pattern, similar to that in seronegative polymyositis, with short, brief motor unit action potentials, early recruitment, with full interference patterns.