Epidemiology of Neuromuscular Manifestations in Patients Carrying the Hiv Virus in Brazil

    


    


    Figure 8: Muscle biopsy of an HIV-positive patient with proximal paresis demonstrating basophilic infiltrate and pink cytoplasmic bodies.

    

Inclusion body myositis is a rare manifestation in HIV-positive patients, where T cells have the function of repairing muscle fiber damage. Thus, the deregulation of T cells, as occurs in HIV infection, may cause less efficiency in repairing these damages, in addition to greater perpetuation of the inflammatory process resulting from the injury to the muscle fiber. Facial and cervical musculature may also be compromised. Treatment with human immunoglobulin may improve symptoms [5].

Another rare form of neuromuscular manifestation is nemaline myopathy. In this case, the immune response against HIV results in the deposition of rod-like structures (called nemaline bodies) and disruption of the Z lines of the muscle fiber. At MRI, edema and fat replacement can be seen affecting the proximal muscles of the upper and lower limbs. Muscle biopsy may demonstrate nemaline deposits. Treatment can be performed with corticosteroids in pulse therapy [13].

Myasthenic syndrome can also occur as a result of HIV infection. Immune dysregulation can result in the formation of antibodies against neuromuscular junction structures. The form of presentation is similar to the general population, with proximal paresis, palpebral ptosis, dysphagia, dysphonia and diplopia, but antibodies against the acetylcholine receptor may be low or absent. The diagnosis is then made by ENMG with repetitive stimulation and a positive response to pyridostigmine. Treatment should continue with venous immunoglobulin, prednisone or cyclophosphamide.

Patients presenting with constitutional symptoms, subacute onset symmetrical proximal paresis may have immune-mediated inflammatory myopathy. The inflammatory mechanism stems from the dysregulation of T cells resulting from HIV infection. Biochemistry may show an increase in CK and treatment can be performed with corticosteroids, azathioprine, methotrexate, cyclophosphamide, cyclosporine and human immunoglobulin [7].

Infectious myopathy or pyomyositis can occur in advanced stages of HIV infection. The main causative agent is Staphylococcus aureus, but other agents such as Toxoplasma, Cryptococcus and Mycobacterium avium have also been reported (ROBINSON-PAPP and SIMPSON, 2009). Patients may present with focal or multifocal pain, muscle swelling, fever, and sepsis. MRI and contrast-enhanced Computed Tomography (CT) and muscle ultrasonography can help in the etiological differentiation of myopathy, as abscesses can be seen in infectious causes [10].

Given these forms of presentation, HIV-positive patients who manifest myopathic symptoms should be investigated by means of biochemical collection, ENMG and, in some cases, muscle biopsy may be necessary. In biochemistry, CK, aldolase, aspartate aminotransferase, alanine aminotransferase and lactic dehydrogenase should be requested. These can be increased in all forms of presentations.

ENMG may show fibrillation, a positive wave, increased insertion activity, early recruitment, and low-amplitude, polyphasic, short-duration motor unit action potentials.

Muscle biopsy may demonstrate characteristic findings in nemaline myopathy, inclusion body myositis, and zidovudine-associated myopathy. In nemaline myopathy, muscle biopsy may show necrosis, inflammation, and red-blue cytoplasmic structures seen on Trichrome Gomori staining. In inclusion body myositis, red annular vacuoles, endomysial infiltrate of CD8+ T cells and macrophages, atrophic fibers and amyloid deposits are seen. Zidovudine-associated myopathy may show torn red fibers, cytochrome C oxidase-negative fibers, accumulation oflipids and glycogen, inflammatory infiltrate and reduced number of mitochondria [4-6].

e) Motor Neuron Disease

Motor Neuron Disease (MND) in HIV-positive patients manifests similarly to the general population and has an incidence of 3.5 cases/1000 patients versus 1 to 2 cases/100,000 per year in individuals not infected with this virus (PRIOR, SONG and COHEN, 2018). Paresis and asymmetric distal atrophy of the limbs, fasciculation, heightened deep reflexes and weight loss mayoccur, as well as trunk signs such as dysphagia, dyspnea and speech alteration. Some characteristics are related to a better prognosis, such as onset at a younger age and evolution in days to weeks. On the other hand, those who have an undetectable viral load at the onset of NMD manifestations have little or no responses.

Compared to the general population, NMD in HIV-positive individuals occurs at a younger age, in general before 40 years of age, presents rapid progression but may partially or completely improve after initiation of ART with drugs that penetrate the CNS. The good therapeutic response with the initiation of ARV treatment suggests a causal relationship between HIV and motor neuron disease.

The pathophysiology of NMD in HIV-infected patients is not well understood. CHERRY et al., 2005, suggest that the mechanism is related to the activation of a retrovirus called Human Endogenous Retrovirus K (HERV-K), in the cortex and anterior cord of the medulla, by HIV proteins. It has been previously described in the literature that in sporadic cases of NMD, there is activation of HERV-K in cortical neurons and anterior horn cells of the medulla.15 Studies involving neuron cultures from experimental animals have shown that activated HERV-K causes degeneration of motor neurons, resulting in symptoms similar to those of NMD. Studies carried out by JOHNSON et al., 2013 demonstrated that the HIV-Tat protein is capable of activating HERV-K and this protein has already been isolated in the brain of HIV-infected individuals.

Regarding the diagnosis, initially, ENMG of the four limbs and paravertebral musculature should be performed. This may demonstrate reduced motor action potential amplitude, fasciculation, fibrillation and positive waves (signs of active denervation) and reduced motor units when assessing recruitment. Clinically, it may be difficult to rule out that upper motor neuron signs are not myelopathy or that second neuron signs are not neuropathy or radiculopathy.

f) Other neuromuscular manifestations

Autonomic symptoms such as dry mouth, postprandial fullness, orthostatic hypotension, diarrhea or constipation, sexual dysfunction, among others, may occur in HIV-infected individuals, but the causal relationship with this virus is uncertain. Some opportunistic infections such as VZV and CMV infection can cause dysautonomic symptoms; The prevalence of autonomic symptoms in HIV positive patients is not known. It is known that it is more severe in the advanced stages of this infection than in the initial stages , GABBAI, CASTELO and OLIVEIRA, in 2013, evaluated the presence of cardiovascular autonomic changes in HIV-positive patients and observed that they are more frequent in advanced stages of the infection. Cardiovascular autonomic neuropathy increases the risk of sudden death in these patients [16].

Regarding antiretrovirals, several classes have already been associated with neurotoxicity. Fortunately many of them are already used less frequently today. Still, many of the neurotoxic effects do not completely resolve after discontinuing ARV use. Therefore, it is important to know these effects and to question the patient about the previous use of ARVs as part of the diagnostic investigation (Chart 1).

Myopathy related to the use of Raltegravir, a new ARV from the class of integrase inhibitors, deserves to be highlighted. It can cause proximal myopathy or just an asymptomatic increase in CK that is not related to dose or time of use. Due to the rarity of this effect, any patient presenting with myopathic symptoms on Raltegravir should be investigated for other causes of myopathic syndrome (Table 1).

Another form of neuromuscular manifestation of HIV is HIV-associated sensory neuropathy (NS-HIV). Small fiber neuropathy is a subtype of sensory neuropathy that has several causes (Chart 3) and is an important challenge for both patients and physicians. This is due to the fact that, even today, there is great difficulty in diagnosing and treating it.

Thin-fiber neuropathy is so named because it predominantly or exclusively affects small-caliber somatic and/or autonomic fibers, RAASING et al., 2021.17 In the peripheral nervous system, the smaller-caliber fibers are the Ad, which have axons with a thin thickness of myelin, and the C fibers, which are fibers whose axons do not have myelin and, therefore, are called unmyelinated. Thus, in pathologies in which fine fibers are affected, we can find alterations related to the functioning of Ad and C fibers.

Sensory neuropathies start with the involvement of fine fibers but can evolve and compromise larger-caliber fibers and thus present a mixed pattern of neuropathy, CASANOVA-MOLLA et al., 2011 [11], Patients who have predominantly fine-fiber neuropathy may have a certain degree of involvement of thick fibers. There is no consensus in the literature about the intensity of impairment of thick fibers that the patient can present and still be considered predominantly involvement of fine fibers.

Clinically, patients may present with “positive” or “negative” sensory alterations or dysautonomia. Sensory symptoms start in the feet and slowly ascend in a length-dependent manner (Figure 9) and may affect the hands. The “positive” symptoms consist of pain, which is the predominant characteristic, and may be reported as “burning”, “stinging”, having an itchy component and may be worse at night, interfering with sleep. The “negative” sensory symptoms can be reported as “numbness”, “tightness” and even a feeling of “cold skin” in the affected limbs [12].

    


    


    Figure 9: length-dependent progression of small-fiber neuropathy.