Association between motor neuron disease and HIV infection: A systematic review of case reports

Abstract

Background

Motor neuron disease (MND) is a well-known group of neurodegenerative diseases, with amyotrophic lateral sclerosis (ALS) being the most common form. Since 1985, a possible association between MND/ALS and HIV infection has been described.

Methods

We performed a systematic review of case reports and case series involving people living with HIV with MND/ALS through PubMed, Bireme, Embase, and Lilacs databases. The risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for Case Reports.

Results

We analyzed 36 articles presenting 88 cases. The mean age was 41.6 years. Antiretroviral therapy (ART) was used by 89.8% and riluzole by 16.9%. First signs and symptoms were similarly present on cervical/upper (25%) and lumbosacral/lower limbs (23.9%), mostly with fasciculations (69.8%) and hyperreflexia (58.8%). MND had a progressive course in 32.9% patients and a clinical improve in 54.6% following ART. The mean survival of the 32 patients who died was 12.3 months and the mean survival of the living patients was 62 months. Respiratory failure was the main cause of death (35.7%).

Conclusions

MND/ALS may present differently in the people living with HIV as a rapidly progressive disease in younger people but with the potential to improve weakness and survival through antiretroviral therapy.

Keywords

Motor neuron disease amyotrophic lateral sclerosis human immunodeficiency virus HIV

Take-home points

• Motor neuron disease in HIV-seropositive patients presents differently than in HIV-seronegative ones.

• Patients with motor neuron diseases should be tested for HIV infection.

• Adequate neurological assessment should be performed for people living with HIV regarding motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and ALS-like syndromes.

• Antiretroviral therapy should be considered an important tool to improve neuromuscular symptoms in people living with HIV with motor neuron disease.

Introduction

Motor neuron disease (MND) is a group of neurodegenerative diseases characterized by progressive and irreversible damage to upper, lower, or both upper and lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of MND. The average age of onset is between 51 and 66 years, and the disease affects men and women in a ratio of 2:1.¹ The average time between the onset of symptoms and death or invasive mechanical ventilation is 24 to 50 months.¹

The clinical course of ALS involves both upper motor neuron signs, such as spasticity and hyperreflexia, and lower motor neuron signs, such as fasciculations, weakness, and muscle wasting.² One-third of patients present with bulbar onset of the disease, with progressive dysarthria, dysphagia, and often with emotional lability.² Patients can also present with cognitive and behavioral impairment. Respiratory insufficiency is the cause of death in 77% of patients.³ There are some criteria for diagnosing ALS, like El Escorial and Airlie House.²

As there is no cure for ALS, symptomatic and supportive treatment is essential for disease management. Thus, healthcare centers usually have a multidisciplinary team that includes neurologists, psychologists, nurses, physical educators, and other professionals, depending on each patient’s needs.⁴

The causes of ALS have not yet been completely elucidated. However, many genetic mutations have been described in ALS. Furthermore, environmental factors such as smoking, toxins, viruses, and epigenetic factors may have a role in ALS development.⁵

Since the 1960s, a possible causal relationship between MND and viral infection has been speculated. The polio virus, HTLV, and HIV have been proposed to cause ALS.⁵ From 1985, case reports of HIV-positive ALS patients began to appear in the literature.⁶ Additionally, HIV infection has been noted in other forms of motor neuron disease.

In the general population, the incidence of ALS is 0.6–3.8 per 100,000 persons-year, and the prevalence is 4.1–8.4 per 100,000 people.¹ A study of 1700 patients living with HIV followed through 13 years found six patients presenting neurological symptoms compatible with an ALS-like disorder, suggesting a higher incidence.⁷ This indicates that the prevalence of ALS is higher in people living with HIV. Although it was calculated through a small population, the prevalence of ALS-like disorder seems to be higher in people living with HIV.

In coexistence with HIV infection, ALS tends to occur in younger patients, progresses rapidly, and may have some degree of improvement after starting antiretroviral therapy (ART).⁵ Despite the prevalence of HIV worldwide, with around 39 million people living with the virus, the literature has been adding little knowledge over the decades about the severity and treatment of associated MND when compared to the general population.⁸

Due to differences in the epidemiology and clinical course of different MNDs in people who are HIV-positive and people who are HIV-negative, there is a need to enhance current knowledge regarding the relationship between HIV and MND/ALS-like disorders. Thus, we performed a systematic review of case reports and case series of people living with HIV with MND in the literature. This article aims to elucidate these patients’ characteristics, clinical manifestations, and management. Furthermore, we also sought to evaluate the influence of ART on neurological deficits.

Materials and methods

Search strategy and inclusion criteria

This systematic review, registered in the International Prospective Register of Systematic Reviews (PROSPERO) under protocol CRD42023475980, adhered to rigorous search methodology. Employing guidelines outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), comprehensive literature searches were conducted to identify relevant articles.⁹

On November 01, 2022, international online databases including PubMed, Bireme, EMBASE, and Lilacs were systematically queried using the following search strategy, in full: (“HIV”) AND (“Motor Neuron Disease” OR “MND” OR “Amyotrophic Lateral Sclerosis” OR “ALS”). Additionally, it should be acknowledged that the search strategy remained consistent across all databases utilized in this study, and both conference-published material and papers published in peer-reviewed journals were considered for inclusion. Thus, inclusion criteria encompassed reports published in English, Portuguese, or Spanish and meeting the following conditions: (a) being a case report or case series describing cases of MND patients with HIV infection; (b) availability in English, Portuguese, or Spanish languages; (c) high quality of evidence, related to the arrangement of information between articles.

As exclusion criteria, case reports, and case series were exclusively chosen over case-control or cohort studies to focus on detailed accounts of individual or small groups of Motor Neuron Disease (MND) patients with HIV infection. While case-control or cohort studies could offer higher evidence levels, they were omitted to emphasize nuanced clinical observations and rare manifestations specific to this population. This approach aims to provide a comprehensive understanding of the disease presentation in people living with HIV, guiding potential diagnostic and therapeutic strategies within this context.

Outcomes of interest

Given that our primary aim is to assess the progression of MND in people living with HIV, we will analyze characteristics such as age at diagnosis, clinical course of the disease, and response to MND after the introduction of ART.

Screening and data extraction

Using Rayyan software, authors deduplicated extracted articles.¹⁰ Then, two researchers evaluated the titles and abstracts independently based on the previously mentioned eligibility criteria. In cases of doubt or disagreement, a third researcher assessed the work to make the final decision. After defining the included articles, the whole text evaluation stage began to decide whether it was eligible. Articles that were not case reports or case series, those written in other languages than English, Spanish, and Portuguese, and articles in which the full text was not available were excluded.

The same two authors also did data extraction. The data extracted were (a) author and year of study, (b) patient’s age, (c) patient’s sex, (d) interval between HIV and ALS diagnosis’, (e) first symptom, (f) location of the first symptom, (g) presence or absence of opportunistic infections, (h) presence or absence of fasciculations, (i) presence or absence of hyperreflexia, (j) presence or absence of respiratory signs, (k) use or not of ART, (l) CD4, (m) HIV viral load, (n) use or not of riluzol, (o) survival and cause of death.

Risk of bias assessment

The quality of the included studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tool for case reports.¹¹ Two researchers independently evaluated the quality of each study, and any divergences were resolved through discussion with a third researcher. The JBI tool includes specific criteria for assessing the methodological quality of case reports and case series.

Results

The search identified 1763 articles after removing duplicates between databases. After applying our inclusion criteria, we identified 36 articles presenting 88 cases included in the review. Figure 1 presents our selection process for studies included in this review. Table 1 presents detailed information about all the cases.

Figure 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

Table 1.

Motor neuron disease in patients with HIV infection: summary of case reports and series of cases.

Author/data	Patient	Sex	AGE	Duration of positive status (months)	CD4	Viral load	First symptoms	Localization of first symptoms	LMN, UMN	ART	RILUZOL	Survival (months)	MND course	Opportunistic infections	CAUSE of death
Hoffman, 1985⁵	1	Male	26	Newly discovered	—	—	Weakness, twitching and cramps in left arm and hand	Cervical	LMN, UMN	No treatment	No	>12, alive	Progressive	Gonorrheal pharyngitis	—
Younger, 1988¹²	1	Male	33	NR	—	—	Gait disorder	Lumbosacral	UMN	NR	No	>9, died	Stabilized	Pneumocystis carinii, candida albicans	Opportunistic infection
Younger, 1988¹²	2	Male	38	NR	—	—	Leg stifness	Lumbosacral	UMN	Zidovudine	No	>5, alive	Stabilized	Herpes zoster	—
Verma, 1990¹³	1	Male	32	Newly discovered	—	—	Lower extremity weakness	Lumbosacral	LMN, UMN	NR	No	24, died	Improvement	Histoplasma capsulatum, CMV and atypical mycobacteria	Opportunistic infection
Huang, 1993¹⁴	1	Male	45	Newly discovered	397	—	Left leg and arm weakness	Cervical and lumbosacral	LMN	Zidovudine	No	Not reported	Progressive	None	—
Casado, 1997¹⁵	1	Male	30	18	-	-	Right hand clumsiness and diffuse fasciculations	Cervical	LMN	NR	No	>16, alive	Progressive	None	—
Galassi, 1998¹⁶	1	Female	30	Unknown	340	-	Limb weakness, muscle wasting, and bulbar signs	Bulbar, cervical and lumbosacral	LMN	Zidovudine, methyl-prednisolone, IVIg	No	3, died	Progressive	None	Not reported
Sastre-Garriga, 2000¹⁷	1	Female	39	Newly discovered	540	22.000	Lower limbs cramps and weakness	Lumbosacral	LMN	NR	No	>4, alive	Progressive	Herpes simplex, mycoplasma	—
MacGowan, 2001¹⁸	1	Female	32	Newly discovered	44	77.900	Generalized weakness, dysarthria, and weight loss	Bulbar, cervical and lumbosacral	LMN, UMN	Zidovudine, lamivudine and nelfinavir	No	>48, alive	Improvement	None	—
Nishio, 2001¹⁹	1	Female	42	108	107	44.510	Dysarthria, dysphonia and dysphagia	Bulbar	LMN	Stavudine, lamivudine, nelfinavir	No	>7, alive	Improvement	None	—
Moulignier, 2001⁷	1	Male	27	Newly discovered	84	-	Left hand weakness, muscle wasting and dyasarthria	Bulbar and cervical	LMN, UMN	Zidovudine	No	6, died	Stabilized	Pneumocystis carinii	AIDS dementia complex
	2	Male	61	72	44	-	Left leg weakness, muscle wasting and cramps	Lumbosacral	LMN, UMN	Zidovudine	No	26, died	Improvement	Mycobacterium avium complex	Disseminated opportunistic infection due to M. avium
	3	Male	29	54	2	-	Left leg weakness and tongue fasciculations	Lumbosacral	LMN, UMN	Zidovudine	No	>14, alive	Improvement	None	—
	4	Male	22	6	123	3.7 log10	Bilateral lower limb weakness, muscle wasting, fasciculations	Lumbosacral	LMN, UMN	Zidovudine, didanosine	No	25, died	Improvement	None	Septic shock
	5	Male	25	28	37	4.9 log10	Left arm weakness, muscle wasting, fasciculations	Cervical	LMN, UMN	Zidovudine, lamivudine	No	52, died	Improvement	None	AIDS dementia complex
	6	Female	40	19	227	3.3 log10	Left arm weakness, mild muscle atrophy	Cervical	LMN, UMN	Zidovudine, zalcitabine, indinavir	No	>40, alive	Improvement	None	—
Zoccolella, 2002²⁰	1	Male	44	Newly discovered	360	34.000	Weight loss, cramps and weakness of both hands	Cervical	LMN, UMN	Zidovudine, lamivudine, nevirapine	Yes	36, died	Progressive	Herpes zoster	Respiratory failure
Von Giesen, 2002²¹	1	Male	44	120	430	12.000	Fasciculations and cramps in both quadriceps muscles	Lumbossacral	(?)LMN	NR	No	Not reported	Stabilized	Herpes zoster	—
Von Giesen, 2002²¹	2	Male	NR	1	447	21.857	Fasciculations, weakness and atrophy	NR	LMN	Zidovudine, lamivudine, nevirapine	No	NR	Progressive	None	—
Pearl, 2003 ²²	1	Male	33	192	110	56.000	Shoulder and upper arm weakness and dyasrthria	Bulbar and cervical	LMN	No treatment	No	1, died	Progressive	None	NR
Calza, 2004²³	1	Male	60	108	579	3.100	Progressive limb weakness, dysarthria, dysphonia, and dysphagia	Bulbar, cervical and lumbosacral	LMN, UMN	Zidovudine, didanosine, nelfanevir	Yes	36, died	Progressive	None	Respiratory failure
Sinha, 2004²⁴	1	Male	37	Newly discovered	170	-	Proximal left upper limb weakness	Cervical	LMN, UMN	Zidovudine, lamivudine and nevirapine	No	>1, alive	Improvement	Tuberculosis	—
Berger, 2005²⁵	1	Male	35	Newly discovered	244	8.315	Weakness of the right shoulder	Cervical	LMN, UMN	Zidovudine, lamivudine and trizivir	No	>36, alive	Stabilized	None	—
Verma, 2006⁶	1	Male	60	132	430	Undetectable	Lower extremities weakness and atrophy	Lumbosacral	LMN, UMN	Zidovudine, lamivudine and saquinavir	Yes	13, died	Progressive	None	Respiratory failure
Verma, 2006⁶	2	Male	59	36	394	Undetectable	Left legs weakness and fasciculations	Lumbosacral	LMN, UMN	Zidovudine, lamuvidine and trizivir	No	76, died	Progressive	None	Respiratory failure
Zúñiga Ramírez, 2006²⁶	1	Male	42	132	562	50	Lower limbs weakness	Lumbosacral	LMN, UMN	Lamuvidine, abacavir, zidovudine, lopinavir, ritonavir	No	>41, alive	Progressive	None	—
Verma, 2008²⁷	1	Male	57	36	618	Undetectable	Stiffiness of legs and gait disorder	Lumbosacral	UMN	Zidovudine, lamivudine, lopinavir, ritonavir, tenofovir	Yes	>36, alive	Stabilized	Pneumocystis carinii	—
Verma, 2008²⁷	2	Male	42	96	219	32.200	Stiffiness of legs and gait disorder	Lumbosacral	UMN	Zidovudine, lamivudine, tenofovir, lopinavir, ritonavir, infuvirtide	Yes	>42, alive	Stabilized	None	—
Henning, 2008²⁸	1	Male	34	Newly discovered	382	-	Left shoulder and upper arm weakness and wasting	Cervical	LMN	ART not described in the article	No	>24, alive	Stabilized	Cryptococcal meningitis	—
Nalini, 2009²⁹	1	Male	34	12	142	-	Upper limbs fasciculations and atrophy	Cervical	LMN	Lamivudine, stavudine and nevirapine	No	>42, alive	Stabilized	None	—
Almeida, 2010³⁰	1	Male	59	60	473	Undetectable	Dysarthria and pathological laughter	Bulbar	UMN	ART not described in the article	No	>36, alive	Progressive	None	—
Kulkantrakorn, 2010 ³¹	1	Male	55	24	245	-	Atrophy and fasciculation of all extremities	Cervical and lumbosacral	LMN, UMN	ART not described in the article	No	>3, alive	Progressive	None	—
Cachia, 2012³²	1	Male	62	144	Normal	Undetectable	Left arm weakness	Cervical	LMN	ART not described in the article	No	Unknown	Progressive	None	—
Orsini, 2012³³	1	Male	56	Newly discovered	300	698	Cramps and fasciculations in left arm	Cervical	LMN	Lamivudine, stavudine and nevirapine (+IVIg for AAN)	No	>48, alive	Progressive	None	—
Lee, 2014³⁴	1	Male	55	Newly discovered	-	-	Upper and lower limb weakness	Cervical and lumbosacral	LMN, UMN	NR	No	>4, alive	Progressive	None	—
Anand, 2014³⁵	1	Male	44	Newly discovered	98	-	Lower limbs weakness	Lumbosacral	LMN, UMN	ART not describied in the article	No	>8, alive	Progressive	None	—
John, 2015³⁶	1	Male	35	Newly discovered	184	101.767	Left lower limb weakness	Lumbosacral	LMN, UMN	Lamivudine, zidovudine and nevirapine	No	>6, alive	Improvement	None	—
Bowen, 2016³⁷	1	Male	29	348	402	Undetectable	Hands and shoulders weakness	Cervical	LMN, UMN	Indinavir, ritonavir, emtricitabine and tenofovir	No	>132, alive	Improvement	None	—
	2	Male	32	24	6	36.924	Bibrahial atrophy and weakness	Cervical	LMN, UMN	Abacavir, lamivudine and dolutegravir	No	>1, alive	Improvement	Pulmonary enterovirus and rhinovirus infections, CMV retinitis and colitis, candida esophagitis, and facial and oral Kaposi sarcoma	—
	3	Male	62	96	889	75	Proximal arm and hand weakness	Cervical	LMN, UMN	Lopinavir, ritonavir, abacavir and lamivudine	No	>1, alive	Improvement	None	—
	4	Male	33	12	467	15.125	Legs atrophy and fasciculations	Lumbosacral	LMN, UMN	Ritonavir, atazanavir, emtricitabine and tenofovir	No	>156, alive	Progressive	None	—
	5	Male	47	60	9	14.362	Fasciculations and weakness in legs	Lumbosacral	LMN, UMN	Raltegravir, emtricitabine and tenofovir	No	>60, alive	Progressive	None	—
Doshi, 2017³⁸	1	Female	NR	Newly discovered	391	-	Dysarthria and proximal weakness	? and bulbar	LMN	NR	No	NR	Progressive	None	—
Lorenzoni, 2018³⁹	1	Male	60	12 after neurological symptoms onset	250	40.636	Dysarthria, weakness on left leg and fasciculations	Bulbar and lumbosacral	LMN, UMN	Zidovudine, lamivudine, efavirenz	No	24, died	Progressive	None	Respiratory failure
Lorenzoni, 2018³⁹	2	Male	45	96	893	Undetectable	Weakness on left arm and fasciculations	Cervical	LMN, UMN	Raltegravir, tenofovir, lamivudine	No	>72, alive	Progressive	None	—
Moodley, 2019⁴⁰	35 patients	18 male/17 female	Average of 40.3	Average of 6.85	Variable	Variable	Variable	Variable	Variable			18 patients died (avarage survival of 8 months); 17 were alive after 120 months	Improvement in 34 patients; progressive in 1 patient	Not described	Variable
Oliveira, 2019⁴¹	1	Male	49	96	332	Undetectable	Right hand weakness	Cervical	LMN	Tenofovir, lamivudine and dolutegravir	Yes	>84, alive	Progressive	Pneumocystosis and disseminated tuberculosis	—
	2	Male	37	84	410	Undetectable	Left hand weakness	Cervical	LMN	Zidovudine, lamivudine and efavirenz	Yes	>12, alive	Progressive	Syphilis	—
	3	Female	38	60	319	1510	Weakness and atrophy of left leg	Lumbosacral	LMN	Zidovudine, lamivudina and atazanavir/ritonavir	No	>84, alive	Stabilized	None	—
Quevedo-Ramirez, 2020⁴²	1	Male	38	Newly discovered	220	67.019	Spastic paraplegian pain in lower limbs and difficult on walking	Lumbosacral	LMN, UMN	ART not described in the article+corticosteroids	No	NR, died	Progressive	Syphilis	NR
Satin, 2021⁴³	1	Male	NR	Unknown	42–150	Elevated	Left hand weakness	Cervical	LMN, UMN	ART not described in the article	No	>24, alive	Progressive	None	—
	2	Male	NR	300	Normal	—	Weakness and atrophy in left upper extremity	Cervical	LMN, UMN	ART not described in the article	Yes	>8, alive	Progressive	None	—
	3	Male	NR	144	Normal	—	Right hand weakness	Cervical	LMN, UMN	ART not described in the article	Yes	>14, alive	Stabilized	None	—
John, 2021⁴⁴	1	Male	50	Newly discovered	70	34.800	Lower limb weakness	Lumbosacral	LMN, UMN	Tenofovir, lamivudine, efavirenz	No	>6, alive	Improvement	Herpes zoster	—

ART: antiretroviral therapy; NR: not reported; LMN: lower motor neuron; UMN: upper motor neuron; CMV: cytomegalovirus.

Among 88 patients recruited in this review (mean age 41.6 years), male predominance was identified in 86.8% (64/88). MND/ALS-like syndrome was the first clinical manifestation related to HIV infection in 19.3% (17/88). In contrast, 75% (66/88) of HIV tests had already been positive before MND. CD4 count and viral load were used as parameters for evaluation and monitoring of immunological status and varied widely: CD4 ranged from 2 to 893 (302 ± 216.3 cells/μl) and viral load between undetectable to 101,767 copies/ml (20,828 ± 26,948 copies/ml).

Furthermore, 89.8% (79/88) used ART at some point during the course of MND, while 2.3% (2/88) remained without treatment. Regarding specific drug treatment for MND, only 16.9% of patients used riluzole (9/53), as shown in Table 2. Opportunistic infections were found in 32% (17/53) of patients. In the 35 cases reported by Moodley et al.,⁴⁰ there were no details regarding riluzole use or opportunistic infections.

Table 2.

Clinical manifestations, treatment and survival of MND patients with HIV infection.

First symptoms	N = 53^a	%
Weakness	40	75.5
Fasciculations	16	30.9
Bulbar	9	16.9
Stiffness	3	5.6
Localization of first symptoms	N = 88
Bulbar	5	5.7
Cervical	22	25
Lumbosacral	21	23.9
Respiratory only	1	1.1
Combination of the above	38	43.1
Not reported	1	1.1
Symptoms	N = 53^a
Fasciculations	37	69.8
Hyperreflexia	31	58.5
Bulbar symptoms	17	32.1
Respiratory symptoms	8	15.1
Cognitive symptoms	4	7.5
MND deficits	N = 53^a
UMN	5	9.4
LMN	16	30.2
LMN, UMN	32	60.3
MND course	N = 88
Progressive	29	32.9
Stabilized	11	12.5
Improvement	48	54.6
Treatment	N = 88
No treatment	2	2.3
Not reported	7	7.9
Treatment	79	89.8
Survival	N = 88
Death	32	36.3
Alive	51	57.9
Not reported	5	5.8
Survival time	Months
Survival time of dead patients (months)	12.3
Survival time of alive patients (months)	62.0
Survival time of all patients (months)	42.8

^aInformation not detailed in the 35 patients of Moodley et al.

Regarding the first signs and symptoms, the most reported topography was cervical/upper limbs (25%; 22/88) and lumbosacral/lower limbs (23.9%; 21/88), according to Table 2. Fasciculations were observed in 69.8% (37/53) of patients, hyperreflexia in 58.8% (31/53), bulbar symptoms in 32.1% (17/53), respiratory symptoms in 15.1% (8/53) and cognitive impairment in 7.5% (4/53). Purely LMN syndrome was observed in 30.2% (16/53) of the cases and purely UMN syndrome in 9.4% (5/53), while LMN and UMN syndrome was present in most of the patients (60.3%; 32/53). The clinical features of the 35 patients described by Moodley et al.⁴⁰ were not fully described.

The course of MND was progressive in 32.9% of the patients (29/88), while improvement was reported in 54.6% (48/88). The mean period of survival after diagnosis was 12.3 months in patients who died and 42.8 months considering all patients and respiratory failure was the most common cause of death in 35.7% (5/14) patients, followed by opportunist infection (28.5%; 4/14) and AIDS complex dementia (14.2%; 2/14). The cause of death was related to MND in 15 of the 18 patients who died in Moodley et al.,⁴⁰ but no more details of the causes were given. Table 2 shows the primary clinical manifestations, treatment, and survival data.

Discussion

In this systematic review, we analyzed 88 cases of motor neuron disease associated with HIV infection. These patients showed particular differences when compared with the general cases. This reinforces the need for an earlier and regular neurological assessment in people living with HIV.

We observed that MND occurs in younger patients when associated with HIV than in the general population. The mean age of MND/ALS-like diagnosis in seropositive patients was 41.6 years old, while in seronegative patients, this age ranges from 51 to 66 years old, with a higher incidence after 65 years.² Besides these age differences, our results show a male-to-female ratio of 2.6:1, a proportion similar to that found in MND epidemiological studies, which report a male-to-female ratio of 2:1 in seronegative patients.¹ Spinal-onset of MND was observed in most of these patients as in the general population rather than the bulbar-onset.^2,45,46

Further, even if the clinical signs and symptoms of MND in people living with HIV are similar to the general population, the epidemiological characteristics seem to be different,^6,39 as well as the progression of the disease and the response to antiretroviral therapy.^7,18,39

These differences must be related to the mechanism by which HIV affects the central nervous system and presents an MND/ALS-like disorder. Pathophysiology is unknown, but it probably involves more than a single mechanism.⁷ Some evidence suggests that the infection infiltrates macrophages and triggers inflammation of microglia and astrocytes, indirectly affecting damage to cortical and spinal anterior horn motor neurons.³⁷ Previous studies show activation of a human endogenous retrovirus K (HERV-K) in brain tissue and anterior horn cells at autopsy of patients with amyotrophic lateral sclerosis^47,48 and is regulated by TAR DNA-binding protein 43 (TDP-43), which is a highly conserved nuclear RNA/DNA binding protein involved in the regulation of RNA processing. TDP-43 is a multifunctional protein and is overexpressed in ALS and other neurodegenerative diseases (Alzheimer’s disease, frontotemporal dementia, and limbic predominant age-related TDP-43 encephalopathy - LATE) and is believed to have an important role in regulating HERV-K expression and contributes to DNA damage and morphological and functional changes consistent with axonal and dendritic injury subsequent neurodegeneration.⁴⁹ Besides, the activity of reverse transcriptase, an enzyme necessary for viral replication, can be found in the brain and blood of ALS seronegative patients.^37,48

This possible influence of HIV on the pathophysiology of MND has been speculated for many decades. Therefore, it was expected that the use of ART would affect the course of the disease. In 2001, the first case of MND was reported in which there was a significant clinical improvement in the neurological condition following the use of ART.¹⁸. In the same year, a case series presented 6 HIV-positive patients with MND who had stabilization or improvement of the clinical symptoms after using ART.⁷ The results of our systematic review are in line with this association. This study found that 54.6% of patients improved their neurological condition, with some recovering significantly. Among these patients, 97.9% used ART. Furthermore, in 12.5% of cases, the clinical condition stabilized. Of these, 81.81% used ART (in the remaining cases, the articles did not specify whether ART was used).

In this review, 32 patients died. The average survival among these patients was 12.3 months. In epidemiological studies, the survival of ALS patients is variable. Some indicate 24–50 months,¹ and others 36–48 months.⁵⁰ Therefore, the survival of dead HIV-positive patients in this review is below the average survival of non-HIV patients. Thus, as has been speculated in previous studies, MND has a faster course in the presence of HIV infection. This reinforces the need for an earlier and regular neurological assessment in people living with HIV. This is yet another factor that supports the hypothesis that HIV influences the pathogenesis of MND.

The primary limitation of our systematic review stemmed from the language inclusion criteria. As other idioms were excluded, a study that met other criteria could be neglected. However, this may not be a solid impairment to this document’s quality since most articles are written in English. This review highlighted the significant variability in clinical characteristics, symptoms, and outcomes among cases of motor neuron disease in people living with HIV, emphasizing the importance of considering heterogeneity in interpreting the results. Recognizing these methodological aspects is crucial for enhancing the validity and reliability of the evidence presented and guiding future research and clinical practices in this complex field.

Conclusion

Although the causal relationship and the influence of the overlap between HIV infection and MND/ALS needs to be further investigated, patients diagnosed or suspected of having MND/ALS-like disorders must be tested for HIV, and those who are HIV-positive would benefit from ART and also multidisciplinary support care for MND/ALS.

Footnotes

Acknowledgements

The authors thanks the Institutional Program of Scientific Research Volunteers of the Federal University of Uberlândia.

Author contributions

D. dos Santos contributed to the manuscript design of the study. J. Fernandes and L. Garcia contributed to the manuscript writing from the systematic literature review. F. Gouhie contributed to the methodological analysis and the written process of the manuscript. R. Campos contributed to the manuscript’s written process. All the authors have reviewed and approved the final version of this manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Leonardo Peixoto Garcia

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