HIV-associated neuromuscular weakness syndrome
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HIV-associated neuromuscular weakness syndrome
David Simpsona , Lydia Estanislaoa , Scott Evansb, Justin McArthurc,
Kendall Marcusd, Melissa Truffad , Brendan Luceyc, Robert Naismithe ,
J Tyler Lonerganf , David Clifforde and the HIV Neuromuscular
Syndrome Study Group*
Objective: To investigate progressive, severe neuromuscular weakness associated
with lactic acidosis in some HIV-infected patients after exposure to nucleoside reverse
transcriptase inhibitors (NRTI).
Methods: HIV-associated neuromuscular weakness syndrome (HANWS) was retro-
spectively identified and classified based on the level of diagnostic certainty: possible
(progressive weakness owing to neuromuscular disease), probable (progressive neuro-
muscular weakness with documented exclusion of confounding causes), or definite
(progressive weakness and electrophysiological or pathological evidence of neuro-
muscular pathology).
Results: Of 69 patients identified with HANWS, 27 had definite HANWS, 19
probable, and 23 possible. In 44 patients with documented follow-up, 16 required
intubation and nine died. There was a marginal association between death and
hyperlactatemia (P ¼ 0.061). At onset of neurological symptoms, 68 were receiving
antiretroviral therapy, including stavudine for 61 (89.7%). Serum lactate level was
elevated (. 2.2 mmol/l) in 30/37 (81%), with a trend towards an association between
hyperlactatemia and stavudine usage (P ¼ 0.087). In 25, neurological symptoms
occurred after antiretroviral therapy discontinuation (median, 14 days). Electrophysio-
logical studies (n ¼ 24) indicated sensorimotor neuropathy in 20 patients and myo-
pathy in three. Nerve biopsy (n ¼ 9) revealed axonal degeneration and inflammation
in three, mixed axonal and demyelinating lesions in three, and primary axonal
neuropathy in three. Of 15 muscle biopsies, three revealed inflammation and four
mitochondrial abnormalities.
Conclusions: A severe neuromuscular weakness syndrome may occur in HIV-infected
individuals. The association with hyperlactatemia and NRTI exposure supports mito-
chondrial toxicity as a pathogenesis. In some, the onset of neurological symptoms
lagged significantly after discontinuation of antiretroviral therapy, suggesting that
different etiological mechanisms may underlie these cases.
& 2004 Lippincott Williams & Wilkins
AIDS 2004, 18:1403–1412
Keywords: peripheral neuropathy, myopathy, lactic acidosis, ARV toxicity, HIV
From the a Mount Sinai Medical Center, New York, the b Harvard School of Public Health, Boston, Massachusetts, c Johns Hopkins
University, Baltimore, Maryland, the d Food and Drug Administration, Rockville, Maryland, the e Washington University School of
Medicine, St Louis, Missouri and the f University of California Medical Centre, San Diego, California USA. *See Appendix for
group members.
Correspondence to Professor D. M. Simpson, Mount Sinai Medical Center, 1 Gustave L. Levy Place, Box 1052, New York, NY
10029, USA.
Received: 27 September 2003; revised: 2 December 2003; accepted: 23 December 2003.
DOI: 10.1097/01.aids.0000131309.70451.fe
ISSN 0269-9370 & 2004 Lippincott Williams & Wilkins 1403
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.1404 AIDS 2004, Vol 18 No 10
Introduction ment, either acute (1–2 weeks) or subacute (. 2
weeks) and affecting either the lower limbs or both
Metabolic and neurological disorders are common lower and upper extremities. HIV-associated neuro-
complications of HIV infection and antiretroviral muscular weakness syndrome (HANWS) was classified
(ARV) therapy [1–3]. Hyperlactatemia may occur in as possible, probable, or definite. Possible HANWS was
association with HIV infection, particularly in the progressive weakness with clinical features consistent
setting of therapy containing a nucleoside reverse with peripheral nerve or muscle disease, with con-
transcriptase inhibitor (NRTI). The frequency of hy- founding causes of weakness present or without doc-
perlactatemia varies widely among studies [4–6] and umentation of medical evaluation to exclude such
has not been found to be a useful clinical marker for conditions. Probable HANWS was appropriate clinical
prediction of development of lactic acidosis syndrome features, with a documented medical and neurological
(LAS). The use of NRTI appears to confer greater risk evaluation excluding other confounding causes of
for the development of LAS [4,5], suggesting that weakness. Definite HANWS was classified as clinical
prolonged toxicity, presumably to mitochondria, leads features of probable HANWS with electrophysiological
to this syndrome. or pathological confirmation of neuromuscular pathol-
ogy. An exploratory analysis focused on estimation.
The Food and Drug Administration (FDA) and several Because of the exploratory nature of the study, poten-
case series have reported a ‘rapidly ascending neuro- tial associations were identified using a significance level
muscular weakness syndrome’ associated with LAS in of 0.10, without adjustment for multiple comparisons.
HIV-infected individuals [7–9]. In the majority of
these patients, dramatic motor weakness develops over
days to weeks, resembling Guillain–Barré syndrome,
and leads to respiratory failure and death in some Results
patients. Diagnostic information from a limited number
of patients has revealed evidence of severe axonal Characteristics of the cohort
neuropathy. Systemic symptoms include nausea, vomit- Sixty-nine patients with HANWS were identified: 32
ing, weight loss, abdominal distention, hepatomegaly, (46%) women, 34 (49%) men, and gender was unspeci-
and lipoatrophy. From FDA surveillance, 22 of 25 fied in three. There were 27 patients with definite, 19
patients developed this syndrome in association with with probable, and 23 with possible HANWS. The
stavudine (d4T) therapy [7], but muscle weakness groups did not differ in age, serum lactate, bicarbonate
worsened even after ARV discontinuation. These level, arterial pH, CD4 cell count or plasma HIV RNA
reports resulted in a ‘Dear Healthcare Provider’ letter (Table 1).
and change in the d4T label. The present study reports
on 69 HIV-infected individuals with progressive neu- Systemic symptoms, including nausea, vomiting, and
romuscular weakness, with emphasis on the electrophy- abdominal pain, were present in 38 (56%) patients, of
siological, histological, and metabolic features of this whom 24 (63%) had documented hyperlactatemia
syndrome. (venous lactate . 2.2 mmol/l). Of the 30 (43%) sub-
jects overall with hyperlactatemia, 19 (63%) had
electrophysiological or pathological evidence of neuro-
muscular pathology: 16 (84%) with neuropathy, and
Methods three (16%) with myopathy. Of seven subjects with
normal lactate levels, two had demyelinating neuropathy.
Cases were identified retrospectively from Medwatch
forms submitted to the FDA through the FDA Adverse The most commonly used ARV agent at the time of
Event Reporting System (AERS) and from collaborat- presentation was d4T, which was taken by 61/69 (88%)
ing authors. The FDA database was searched using patients in the total cohort and 24/27 (89%) patients
the following search terms: neuromuscular weakness with definite HANWS (Table 2). The median duration
and lactic acidosis/symptomatic hyperlactatemia. These of d4T use was 10.5 months (range, 1–71 months).
events were required to occur within 4 to 5 weeks of Dosage and adherence information was not available.
each other, in order to meet the FDA’s case definition The median lactate level of those on d4T (5.30 mmol/l;
of ‘ascending neuromuscular weakness syndrome’. The n ¼ 33) was higher than in those not on d4T
Medwatch forms were reviewed to supplement and (2.55 mmol/l; n ¼ 4) (P ¼ 0.087). There was no associa-
confirm data present in the AERS database. tion between lactate level and the duration of d4T use.
Collaborative authors identified individual patients Sensory symptoms (paresthesias, dysesthesias, and
based on the following criteria: new onset of limb numbness) were reported in 22 (32%) patients. Eight
weakness with a neuromuscular cause in an HIV- (12%) had bulbar symptoms, including facial nerve
infected individual, with or without sensory involve- palsy, eye movement abnormalities (e.g., ophthalmo-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.HIV neuromuscular syndrome Simpson et al. 1405
Table 1. HIV-associated neuromuscular weakness syndrome: age and laboratory findings.
Possible Probable Definite Total P valuea
Number 23 19 27 69
Median age [years (n)] 38 (20) 43 (18) 41 (27) 42 (64) 0.32
Median lactate [mmol/l (n)] 6.10 (4) 4.20 (11) 5.35 (22) 4.90 (37) 0.84
Median arterial pH (n) 7.29 (2) 7.32 (3) 7.30 (9) 7.30 (14) 0.89
Median bicarbonate [mmol/l (n)] 17.30 (4) 16.90 (10) 18.00 (11) 17.00 (24) 0.89
6
Median CD4 cell count [ 3 10 cells/l (n)] 244 (6) 200 (9) 168 (18) 200 (33) 0.21
Median HIV viral load (log10 copies/ml (n)] 3.93 (5) 1.93 (6) 2.30 (15) 2.30 (26) 0.21
a
Kruskal–Wallis test.
Table 2. HIV-associated neuromuscular weakness syndrome: antiretroviral drug usage at time of
presentation.
Drug use [No. (%)]
Antiretroviral
drug Possible (n ¼ 23) Probable (n ¼ 19) Definite (n ¼ 27) Total (n ¼ 69)
Nucleoside reverse transcriptase inhibitor
Stavudine 21 (91%) 16 (84%) 24 (89%) 61(88%)
Lamivudine 13 (57%) 9 (47%) 12 (44%) 34 (49%)
Didanosine 5 (22%) 7 (37%) 15 (56%) 27 (39%)
Zidovudine 2 (8.7%) 2 (10%) 3 (11%) 7 (10%)
Abacavir 2 (8.7%) 2 (10%) 0 4 (58%)
Tenofovir 1 (4%) 0 0 1 (1%)
Emitricitabine 1 (4%) 0 0 1 (1%)
Non-nucleoside reverse transcriptase inhibitor
Efavirenz 5 (22%) 5 (26%) 5 (18%) 15 (22%)
Nevirapine 4 (17%) 2 (10%) 2 (7%) 8 (11%)
Delavirdine 1 (4%) 0 0 1 (1%)
Protease inhibitor
Indinavir 4 (17%) 3 (16%) 4 (15%) 11 (16%)
Ritonavir 5 (22%) 6 (32%) 5 (18%) 16 (23%)
Lopinavir 3 (13%) 3 (16%) 4 (15%) 10 (14%)
Nelfinavir 2 (8.7%) 1 (5%) 6 (22%) 9 (13%)
Amprenavir 0 2 (10%) 0 2 (3%)
Atazanavir 0 0 3 (11%) 3 (4%)
Saquinavir 2 (8.7%) 1 (5%) 0 3 (4%)
plegia, nystagmus, ptosis), dysphagia, and dysarthria. documented follow-up, 16 (36%) had improvement of
Areflexia was present in 12 (17%). By definition, all their neurological condition. The recovery period
patients had limb weakness. The rate of progression of ranged from 2 to 17 months (median follow-up, 3.75
weakness ranged from 1 to 200 days. Of the definite months), and the degree of recovery varied from mild
cases with adequate data, weakness was acute (< 2 improvement to complete mobility. Nineteen patients
weeks) in 14 patients and subacute in eight (range, 17– had substantial residual neurological deficits, marked by
60 days). Neurological symptoms occurred after ARV severe limb weakness, even after a prolonged period
drug discontinuation in 25 patients (median, 14 days), (median follow-up, 3.5 months; range, 1–12). Sixteen
prior to drug discontinuation in 14 (median, 19.5 days), patients had respiratory failure requiring ventilatory
and on the same day as discontinuation in eight. Of 22 support. Nine (16%) patients died (median, 30 days;
patients with LAS symptoms, 11 had ARV therapy range, 3–104), of whom six had elevated lactate levels
discontinued on the day of presentation with these and two had definite HANWS. Mortality was associated
symptoms, while seven had ARV drugs continued for a with lactate level (death, 10.08 mmol/l; survival, 4.40;
median of 30 days (range, 5–90). Four patients had P ¼ 0.061). Exploratory multivariate modeling revealed
ARV therapy discontinuation prior to presentation of a marginal association between mortality and lactate
systemic symptoms. levels . 6 mmol/l [estimated odds ratio (OR), 12.4],
and corticosteroid use (estimated OR, 24.3).
Various treatments were provided for the metabolic and
neurological symptoms, including intravenous immuno- Definite HIV-associated neuromuscular
globulin in 12 (17%), vitamins B1 and B12 in 10 (14%), weakness syndrome
corticosteroids in nine (13%), carnitine or acetylcarni- Nerve conduction and electromyography studies in 24
tine in eight (11%), coenzyme Q10 in three (4%), and patients revealed sensorimotor polyneuropathy in 20
plasmapheresis in three (4%). Of 44 patients with (Table 3). Findings were primarily axonal in 13,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.1406
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
AIDS 2004, Vol 18 No 10
Table 3. Definite HIV-associated neuromuscular weakness syndrome: clinical, electrophysiological and histological findings.
Patient
[age (years) Antiretroviral Lactate
and gender] drug (mmol/l) Systemic symptoms/findings Neurological findings Electrophysiology Histology
1 (49, F) d4T, ddI, AZT 4.1 Nausea, vomiting, abdominal pain Sensorimotor polyneuropathy Axonal neuropathy Nerve: inflammatory axonal
lesions
Muscle: massive acute
denervation atrophy
2 (23, F) d4T, 3TC, ATZ 15.6 Nausea, vomiting, abdominal pain; Paresthesias, pain; marked proximal Axonal polyneuropathy Nerve: severe axonal and
hepatic steatosis cardiomyopathy weakness myelin pathology
3 (59, M) d4T, ddI, IDV 7.7 Nausea, vomiting, diarrhea, abdominal Progressive muscle weakness; areflexia; Severe axonal polyneuropathy Not done
pain, weight loss; hepatomegaly; truncal paraparesis
obesity; peripheral fat atrophy
4 (66, M) d4T, ddI, IDV 8.6 Nausea, vomiting, weight loss; Symmetrical muscle weakness; areflexia; Severe axonal polyneuropathy Not done
hepatomegaly; facial fat atrophy paraparesis
5 (43, M) d4T, ddI, IDV, 19.7 Nausea, vomiting, malaise, weight loss; Rapidly progressive muscle weakness Severe axonal polyneuropathy Not done
RIT hepatomegaly; facial fat atrophy with areflexia
6 (29, F) d4T, ddI, EFV 17 Weight loss; hepatic steatosis Ascending paralysis; tetraplegia; Axonal polyneuropathy Not done
diaphragmatic paralysis
7 (36, F) d4T, 3TC, NFV 11.5 Weight loss; fatty liver; elevated Tetraplegia Axonal and demyelinating Nerve: severe demyelination,
pancreatic enzymes neuropathy minor axonal lesions,
endoneurial and perineurial
edema and inflammation
Muscle: normal
8 (1, M) ddI,AZT, NFV 7.11 Elevated liver function tests; renal Profound motor delay; areflexia Not done Muscle: generalized atrophy
tubular acidosis and fiber size variation;
sarcomeric disarray and
myofibril loss; mitochondrial
abnormalities with
normalization after ARV drug
discontinuation (see text)
9 (40, M) AZT, 3TC, IDV NA NA Progressive, proximal upper extremity Axonal neuropathy Not done
weakness; ptosis; dysarthria and
dysphagia
10 (43, M) d4T,AZT, . 20 Nausea, vomiting Lower extremity weakness Polyradiculopathy Not done
3TC,NVP NFV
11 (48, F) d4T, ddI Lactic Dyspnea Quadriparesis; areflexia; optic Not done Nerve: severe axonal lesions;
acidosis neuropathy inflammation
NOS Muscle: mild muscle fiber
atrophy; fat accumulation;
abnormalities in tissue
oxidative phosphorylation
(complexes I, III and IV)Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
12 (41, M) d4T, ddI, LOP/ 3.6 None Pain, paresthesias, weakness Axonal neuropathy Nerve: axonal neuropathy
RITNVP
13 (42, M) d4T, ddI, EFV 5 Nausea, fatigue Painful neuropathy; profound weakness; Not done Nerve: mild chronic axonal loss
elevated CPK Muscle: inflammatory
myopathy
14 (41, F) d4T, ddI, 3TC, 0.7 Nausea, vomiting, abdominal pain Painful paresthesias; ascending Demyelinating neuropathy Muscle: myofiber atrophy
LOP/RIT quadriparesis; areflexia
15 (38, M) d4T, ddI, PI, 5.0 Nausea, vomiting, abdominal pain Progressive weakness Axonal neuropathy Muscle: type II myofiber
NOS atrophy and rare basophilic
degenerating fibers
16 (25, F) d4T, ddI, LOP/ 7.4 Abdominal pain, vomiting Painful paresthesias; progressive Severe sensorimotor axonal Nerve: decreased large and
RIT weakness; nystagmus, ophthalmoplegia; polyneuropathy; myopathy small myelinated fibers; axonal
encephalopathy degeneration
Muscle: moderate fiber size
variation; rare angulated
atrophic fibers; ragged red fibers
and absent cytochrome oxidase
staining (Figs 1b and 1c)
17 (32, F) d4T, 3TC, ATZ, 6.4 Vomiting, anorexia Hypesthesia of hands and feet; rapidly Polyneuropathy Not done
progressive weakness
18 (29, F) d4T, 3TC, EFV 4.5 Fatigue; elevated liver function tests; Weakness; myalgias; numbness Axonal polyneuropathy Muscle: normal
hepatic cytolysis
19 (23, F) d4T, ddI NA None Tetraparesis Demyelinating and axonal Nerve: axonal neuropathy
polyneuropathy
20 (44, M) d4T, ddI, EFV, 5.3 None Proximal weakness; elevated CPK Myopathy Muscle: severe inflammatory
HU myopathy
21 (39, F) d4T, 3TC, DV, 12.5 Nausea, vomiting, abdominal pain; Numbness, paresthesias; progressive limb Severe, mixed axonal and Not done
NFV fatigue weakness; areflexia demyelinating sensorimotor
polyneuropathy
22 (44, M) d4T, 3TC, NLFV 1.2 None Numbness; ascending weakness Axonal polyneuropathy Skin biopsy: depletion of
mitochondria
23 (34, F) None 0.7 None Numbness, paresthesias; ascending Demyelinating neuropathy Not done
HIV neuromuscular syndrome Simpson et al.
weakness
24 (30, F) d4T, ddI, EFV ‘High’ Nausea, vomiting; elevated liver Rapidly progressive weakness Axonal neuropathy Not done
function tests
25 (45, F) d4T, 3TC, EFV 3.9 Nausea, vomiting, weight loss Progressive lower extremity weakness Myopathy Muscle: rounded muscle fibers;
increased fiber size variation
26 (51, F) d4T, ddI, HU 2.3 Nausea Progressive leg weakness; distal sensory Axonal and demyelinating Muscle: inflammation; rare
loss polyneuropathy ragged red fibers
27 (47, F) d4T, 3TC, EFV NA None Distal paresthesias; progressive weakness Axonal and demyelinating Not done
polyneuropathy
M, male; F, female; NA, not available; NOS, not otherwise specified (as reported by FDA); ARV, antiretroviral drug; ATZ, atazanavir; AZT, zidovudine; d4T, stavudine; ddI, didanosine; 3TC,
lamivudine; EFV, efavirenz; HU, hydroxyurea; IDV, indinavir; LOP/RIT, lopinavir/ritonavir combination; NVP, nevirapine; NLFV, nelfinavir; RIT, ritonavir; CPK, creatine phosphokinase.
14071408 AIDS 2004, Vol 18 No 10
demyelinating in two, mixed in four, and undefined in
one. One patient had polyradiculopathy; two had
myopathy, and one had mixed neuropathy and myo-
pathy. Electrophysiological results for six patients are
presented in Table 4. Nerve biopsy in nine subjects
paralleled electrophysiological findings, with prominent
axonal degeneration in three and demyelinative changes
in three. Three nerve biopsies revealed inflammatory
infiltrates (endoneurial in two and unspecified in one).
Muscle biopsy in 15 patients indicated generalized
myofiber atrophy in three and inflammatory infiltrates
in three (Fig. 1A). Four muscle biopsies revealed
evidence of mitochondrial dysfunction, including
ragged red fibers (Fig. 1B), abnormalities in respiratory
chain enzymes, and mitochondrial DNA depletion. Fig. 1. Muscle biopsy of index case 1. (A) Focal lymphocytic
The patient with the latter findings (Patient 8, Tables 3 infiltration in perimysium and endomysium; numerous small
and 4) was the subject of a previous case report [10], rounded muscle fibers, some basophilic, are present (hema-
describing an infant presenting with profound motor toxylin and eosin stain; bar ¼ 25 ìm). (B) Ragged red fibers;
delay, hypotonia, and areflexia, with lactic acidosis. the accumulations of red staining material (arrow) represent
Muscle biopsy revealed poorly defined mitochondria, mitochondrial proliferation (Gomori trichrome stain;
with disorganized cristae and dense irregular granules. bar ¼ 14 ìm). (C) Absent cytochrome oxidase staining in
scattered muscle fibers (arrow) (bar ¼ 23 ìm). (D) Increased
There was 62–89% reduction in the activities of four
succinate dehydrogenase stain in many small rounded mus-
respiratory chain enzymes on spectrophotometric mus-
cle fibers (bar ¼ 23 ìm).
cle analysis, and a 79% depletion of muscle mitochon-
drial DNA on quantitative Southern blot analysis.
These findings normalized after cessation of ARV
therapy (didanosine, zidovudine, and nelfinavir). Two 106 copies/ml. She had acalculous cholecystitis, with
index cases are described. mildly elevated hepatic transaminases. ARV drugs were
discontinued and this was followed by improvement in
Case 1 (Patient 16) gastrointestinal symptoms. During the next 3 weeks,
Patient 16 was a 25-year-old HIV-infected woman she experienced progressive severe weakness.
who developed insidious progression of a painful distal
neuropathy following 6 months of treatment with d4T, On readmission, she had marked psychomotor retarda-
didanosine, and lopinavir/ritonavir (Tables 3 and 4). tion, inattention, and poor memory. There was end-
She also had abdominal pain and vomiting, for which gaze nystagmus in all directions and left-gaze paresis.
she was hospitalized. Venous lactate level was 7.4 She had profound proximal muscle weakness with
mmol/l (normal, , 2.2 mmol/l), CD4 cell count was absent reflexes. She needed assistance to stand and was
85 3 106 cells/l, and plasma HIV RNA was 1.2 3 unable to walk. Sensory examination revealed a moder-
Table 4. Electrophysiological results
Nerve conduction study
Patient Motor nerve Sensory nerve Electromyography
14 CV: LE absent; UE focal slowing, segmental CV: LE absent; UE severe slowing Fibrillation potentials; reduced recruitment
conduction block Amp: LE absent; UE moderately low
Amp: LE severely low; UE normal
16 CV: normal CV: absent Fibrillation potentials; myopathic; reduced
Amp: normal Amp: absent recruitment
20 CV: normal CV: normal Myopathic
Amp: normal Amp: normal
21 CV: LE slow; UE borderline CV: LE borderline; UE mildly slow Fibrillation potentials; reduced recruitment
Amp: low Amp: LE low; UE absent
23 CV: markedly slow CV: LE normal; UE absent ND
Amp: LE low; UE borderline low Amp: LE normal; UE absent
27 CV: mildly slow CV: mildly slow Fibrillations; reduced recruitment
Amp: markedly low Amp: markedly low
CV, conduction velocity; Amp, amplitude; UE, upper extremities; LE, lower extremities; ND, not done.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.HIV neuromuscular syndrome Simpson et al. 1409 ate, symmetrical stocking-glove pattern reduction to all episodes of tachypnea, which did not require intuba- modalities. Vital capacity was 1.2 litres, with a negative tion, tachycardia, and intermittent hypotension. Peak inspiratory force of 28 cmH2 O. serum lactate was 19.1 mmol/l. Blood chemistry was normal, except for aspartate trans- She had profound limb weakness early after admission. aminase (53 U/l). Venous lactate was 5.7 mmol/l and Neurological examination revealed severe weakness in creatine kinase was normal. Cerebrospinal fluid analysis all extremities; decreased pinprick, vibration, and pro- and magnetic resonance imaging of the brain with prioception with a distal predominance; and general- gadolinium were normal. Nerve conduction studies ized areflexia. Nerve conduction studies revealed revealed normal motor nerve values, with absent evidence of generalized, severe, mixed axonal and sensory nerve action potentials. Electromyography re- demyelinating sensorimotor polyneuropathy. She was vealed fibrillation potentials and brief, small-amplitude treated with intravenous immunoglobulin. Her sys- motor unit action potentials, consistent with irritative temic symptoms improved, with reduced nausea and myopathy. Sural nerve biopsy showed a prominent vomiting, and improvement in metabolic values. Lac- decrease of large and small myelinated fibers, with tate levels declined to 2.4 mmol/l. However, her axonal degeneration. Muscle biopsy revealed moderate neurological status remained unchanged, despite 10 myofiber size variation, with scattered regenerating and days of intravenous immunoglobulin infusion. On the degenerating fibers, and rare angulated atrophic fibers. third week of hospitalization, she was discharged to a There was also myofiber vacuolation, with ragged red rehabilitation center, unable to ambulate indepen- fibers, and reduced-to-absent cytochrome oxidase dently. staining (Fig. 1). She had progression of limb weakness, with stable respiratory function. Treatment included intravenous Discussion immunoglobulin and methylprednisolone, thiamine, folate, multivitamins, riboflavin, and coenzyme Q. She This study reports on a series of 69 HIV-infected was restarted on lopinavir/ritonavir and amprenavir. patients with progressive weakness and metabolic ab- Within 2 weeks, she had marked improvement in eye normalities: HANWS. Most patients with electrophy- movements, respiratory function, and limb strength. siological or pathological evidence of nerve or muscle Over subsequent months, strength improved to allow disease (i.e., definite HANWS) had hyperlactatemia independent ambulation. (20/27), and the mortality rate was 13%. Case 2 (Patient 21) Neurological manifestations were variable, reflecting a Patient 21 was a 39-year-old HIV-infected woman, spectrum of neuromuscular pathology, including a with a CD4 cell count of 167 3 106 cells/l and HIV rapidly progressive sensorimotor polyneuropathy asso- RNA , 40 copies/m who was started on d4T, lamivu- ciated with areflexia, resembling the ‘ascending neuro- dine, and indinavir (Tables 3 and 4). After 1 year, she muscular weakness syndrome’ reported by Marcus et al. developed nausea, vomiting, and abdominal pain. Ten [7] of the FDA. Other patients developed subacutely days later, she developed slurred speech and generalized progressive proximal muscle weakness, and elevated weakness, for which she was hospitalized. Neurological serum creatine kinase, consistent with a myopathic examination was normal. Head computed tomography, process. Electrophysiological and pathological findings electromyography, carotid duplex ultrasound, and confirmed primary pathology of peripheral nerve, cerebrospinal fluid analysis were normal. The gastro- muscle, or both in most subjects with studies per- intestinal complaints persisted, prompting change of formed. While several patients had features of primary indinavir to nelfinavir; after 2 weeks, all ARV medica- demyelination, consistent with the most common form tions were suspended. After a further 6 days after, she of Guillain–Barré syndrome (i.e., acute inflammatory presented with complaints of anorexia, weight loss, demyelinating polyneuropathy), most had primary ax- abdominal pain, fatigue, and dyspnea, in addition to onal pathology. This disorder resembles the axonal persistent nausea and vomiting. She also complained of form of Guillain–Barré syndrome, which has a worse arm and leg numbness and tingling, which had been prognosis than the demyelinating type [11]. present for the past 2 weeks. Admission laboratory results revealed serum lactate 12.5 mmol/l, bicarbonate Hyperlactatemia associated with HIV infection and 10 mEq/l (10 mmol/l), and anion gap 28. Arterial ARV therapy has been widely reported and is a life- blood gas analysis on room air showed pH 7.16, threatening disorder [6,12,13]. The frequency of hy- bicarbonate 2.7 mEq/l, and partial pressure of 8 mmHg perlactatemia has been variable among series and is for carbon dioxide and 145 mmHg for oxygen. She associated with prolonged use of NRTI therapy [4,14]. was treated with intravenous fluids and bicarbonate for The neurological features associated with hyperlactate- lactic acidosis. Over the following days, she had mia and LAS are not well characterized. Several authors Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1410 AIDS 2004, Vol 18 No 10
have provided limited neurological data in the context lar disease, particularly immune-mediated mechanisms.
of the systemic and metabolic abnormalities of LAS Both inflammatory demyelinating polyneuropathy and
[12]. Only one patient has had description of a detailed inflammatory myopathy occur in HIV-infected patients
neurological examination, and few patients have had and were reported before the availability of ARV
electrophysiological or pathological data reported therapy [29,30]. Notably, these disorders are most
[6,9,12,15,16]. The results support a severe axonal common at seroconversion or in early HIV infection,
neuropathy in most patients, although myopathic fea- when immune activation is likely. HIV infection alone
tures were also noted on muscle biopsy in several may impair mitochondrial function [17], and ARV
others [6,12,15,16]. effects may be additive or synergistic. Morgello et al.
[31] reached a similar conclusion in an analysis of
The pathophysiological mechanism underlying NRTI- muscle biopsies in HIV-infected patients with myo-
associated LAS is not clear. Mitochondrial toxicity pathy, showing similar pathological evidence of mito-
likely explains at least some components of this chondrial abnormalities in subjects exposed or
syndrome [17,18]. Cote et al. [17] reported a reduced unexposed to zidovudine.
ratio of mitochondrial to nuclear DNA in HIV-
infected subjects with NRTI-associated LAS. The The time course of events in our subjects is notable.
relationship of HANWS and LAS is also unclear. In There was a delay from the time of LAS presentation,
vitro and animal data suggest that peripheral neuropathy and consequent ARV drug discontinuation, to the
caused by NRTI toxicity may be mediated by mito- onset of neurological symptoms in more than half of
chondrial mechanisms, particularly because of the the patients for whom these data are available. This
propensity of these drugs to inhibit mitochondrial suggests that patients with hyperlactatemia or lactic
DNA gamma-polymerase [19]. Peripheral nerves of acidosis must be closely followed for the development
HIV-infected patients treated with zalcitabine had of neurological symptoms, particularly after disconti-
greater morphological and molecular evidence of nuation of ARV drugs, and improvement of systemic
abnormal mitochondria in the axoplasm and Schwann symptoms. It is possible that recovery in mitochondrial
cells than seen in patients not taking this drug [20]. function following ARV drug discontinuation may
Additionally, a higher percentage of mitochondrial trigger immunological mechanisms, such as cytokine
DNA depletion (80%) was noted in the zalcitabine dysregulation, leading to neuromuscular pathology
group. Brew et al. [21] reported that serum lactate [32,33]. Notably, several nerve and muscle biopsies in
levels are elevated in patients with d4T-associated our patients contained inflammatory infiltrates, consis-
neuropathy. Mitochondrial myopathy with lactic acido- tent with an immune-mediated process.
sis has also been reported with zidovudine [22,23].
Women are over-represented in several series of
Fialuridine, a NRTI studied for the treatment of NRTI-associated lactic acidosis compared with the
hepatitis B, produced a syndrome of severe multisystem general population of HIV-infected patients [12]. Simi-
toxicity, including lactic acidosis, hepatic failure, per- larly, 46% of the patients in our series are women.
ipheral neuropathy, and myopathy [24]. This agent Additionally, women constituted 50% of patients with
caused irreversible, severe, mitochondrial and cellular hyperlactatemia, and 42% of those with both hyperlac-
changes on human myotubule cultures [25]. Myopathy tatemia and definite HANWS. Reasons for this gender
and peripheral neuropathy may occur in HIV-sero- preference are not clear.
negative individuals with inherited or sporadic mito-
chondriopathy [26,27]. Notably, four of our subjects There are several limitations of the current study. Since
had evidence of mitochondrial pathology on muscle this an initial description of an entity that is not well
biopsy. It is not clear why mitochondrial pathology understood, we included subjects that met our minimal
was not evident in all muscle biopsies. It is possible that clinical definition of the neurological aspects of the
sampling variability or tissue-specific mitochondrial syndrome. Information was retrospectively collected
pathology may be responsible. Alternatively, genetic from multiple sources, resulting in non-standardized
factors may predispose patients to additive neurotoxi- information. Complete datasets are not available for all
city of mitochondrial toxins. For example, Cuban patients, particularly lactate level, precluding adequate
blindness syndrome is more likely to develop in pa- comparison between those with and without hyperlac-
tients with pre-existing mitochondrial mutations [28]. tatemia. Recognizing that the precision of diagnosis
varied between subjects, based on the availability of
While mitochondrial toxicity is likely to underlie ancillary tests and exclusion of confounds, we per-
NRTI-associated lactic acidosis, it is uncertain that the formed separate analyses of the definite and probable
neuromuscular disorders are caused by this mechanism. groups alone. These results are similar to those of the
There is potentially interplay between primary HIV- entire cohort, including those with possible HANWS.
induced effects and those linked to ARV drug toxicity. We explored several associations, each using a 0.10
HIV itself may trigger pathways inducing neuromuscu- significance level without adjustment for multiple com-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.HIV neuromuscular syndrome Simpson et al. 1411
parisons. Therefore, results should be interpreted with syndrome that occurs in severely ill patients, termed
caution. Data summaries and analyses were performed critical illness neuromyopathy [37–40]. It must be
on non-missing data with no imputation. Systematic determined from prospective and case–control studies
missing data may have influenced our results. how HANWS fits into the spectrum of neurological
disorders that occur in HIV infection, and whether
Importantly, most of our patients had exposure to NRTI exposure and lactic acidosis represent specific
ARV drugs, including NRTI. We did not explore distinguishing features. This understanding is crucial in
comparative features of the comparison groups (i.e., guiding clinicians in the recognition and management
ARV drug-treated patients without neuromuscular of these disorders. A data collection effort for cases of
weakness, or ARV drug-naive HIV-infected indivi- HANWS, available to all clinicians, is ongoing in the
duals with neuromuscular disease). The study of such Neurological AIDS Research Consentium (http://
comparison groups is of particular importance since www.neuro.wustl.edu/narc/).
neuromuscular disorders, such as Guillain-Barré syn-
drome and myopathy, may occur in HIV-seropositive
individuals independent of ARV therapy. The over-
representation of subjects with hyperlactatemia and Acknowledgements
NRTI exposure in our series may, in part, reflect
acquisition bias, particularly since the FDA, which is We thank Drs Alan Pestronk for pathological speci-
the source of several of our cases, mandated that lactic mens, Susan Morgello for review of biopsies, and John
acidosis must be present with neuromuscular weakness Griffin for his review of the manuscript.
in order to meet their case definition [7]. Furthermore,
the reported association of d4T with lactic acidosis may Sponsorship: This study was supported by NIH grants
have led to more aggressive screening of lactate levels K24NS02253 (DS), NS44807 (JCM), NS26643 (JCM),
in patients receiving d4T. NS44807 (JCM) U01NS32228-08A1, and U01A127667.
There are no prospective studies or case–control series
documenting the occurrence of HANWS, with or
without lactic acidosis. If one speculates an association References
with NRTI therapy, it is notable that these cases have 1. Schambelan M, Benson C, Carr A, Currier JS, Dube MP, Gerber
been reported only since 1998. Didanosine was ap- JG, et al. Management of metabolic complications associated
proved by the FDA in 1991 and d4T in 1994, and with antiretroviral therapy for HIV-1 infection: recommenda-
tions of an International AIDS Society-USA panel. J AIDS 2002,
both have been in widespread use since that time. 31:257–275.
2. Simpson D, Tagliati M. Neurologic manifestations of human
immunodeficiency virus infection. Ann Intern Med 1994,
The pitfall of attributing organ system toxicity to a 121:769–785.
specific ARV agent is illustrated by experience with 3. Simpson D, Tagliati M. Nucleoside analogue-associated periph-
zidovudine and myopathy. In 1990, a case series was eral neuropathy in human immunodeficiency virus infection.
J Acquir Immune Defic Syndr Hum Retrovirol 1995, 9:153–161.
reported of HIV-infected patients with a polymyositis- 4. John M, Moore C, James I, Nolan D, Upton RP, McKinnon EJ,
like syndrome [34]. All were receiving zidovudine. et al. Chronic hyperlactatemia in HIV-infected patients taking
Muscle biopsies revealed ragged-red fibers and other antiretroviral therapy. AIDS 2001, 15:717–723.
5. Brinkman K. Hyperlactatemia and hepatic steatosis as features
evidence of mitochondrial pathology. However, this of mitochondrial toxicity of nucleoside analogue reverse tran-
and several other similar case series were retrospective, scriptase inhibitors. Clin Infect Dis 2000, 31:167–169.
and few included zidovudine-untreated control groups. 6. Gerard Y, Maulin L, Yazdanpanah Y, de la Tribonniere X, Amiel
C, et al. Symptomatic hyperlactatemia: an emerging complica-
In two placebo-controlled trials of zidovudine therapy, tion of antiretroviral therapy. AIDS 2000, 14:2723–2730.
there was no difference in the occurrence of myopathy 7. Marcus K, Truffa M, Boxwell D, Toerner J. Recently identified
in subjects regardless of zidovudine exposure [35,36]. adverse events secondary to NRTI therapy in HIV-infected
individuals: cases from the FDA’s adverse event reporting system
These results indicate that one must be cautious in (AERS). Ninth Conference on Retroviruses and Opportunistic
attributing toxicity to a specific ARV agent based solely Infections. Seattle, February 2002 [abstract LB14].
on selected case series. 8. Galera C, Redondo C, Pozo G. Symptomatic hyperlactatemia
and lactic acidosis syndrome in HIV patients treated with
nucleoside analogue reverse transcriptase inhibitors. First Con-
There are numerous central and peripheral neurological ference on HIV Pathogenesis and Treatment. Buenos Aires, 2001.
9. Verma A, Roland M, Jayaweera D, Kett D. Fulminant neuropathy
disorders that may present with rapidly progressive and lactic acidosis associated with nucleoside analog therapy.
weakness. These may be associated with HIV infection, Neurology 1999, 53:1365–1369.
independent of ARV therapy, and have different 10. Church J, Mitchell W, Gonzalez-Gomez I, Christensen J, Vu TH,
Dimauro S, et al. Mitochondrial DNA depletion, near-fatal meta-
pathogeneses and treatment. HANWS appears to re- bolic acidosis, and liver failure in an HIV-infected child treated
present a syndrome rather than a distinct pathological with combination antiretroviral therapy. J Pediatr 2001,
entity, with features spanning a spectrum of neuromus- 138:748–751.
11. Feasby T, Gilbert J, Brown W, Bolton CF, Hahn AF, Koopman WF,
cular disorders, including peripheral neuropathy, myo- et al. An acute axonal form of Guillain–Barré polyneuropathy.
pathy, and mixed pathology. This is reminiscent of a Brain 1986, 109:1115–1126.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.1412 AIDS 2004, Vol 18 No 10
12. Falco V, Rodriguez D, Ribera E, Martinez E, Miro JM, Domingo P, associated myopathy: analysis of 11 patients. Ann Neurol 1988,
et al. Severe nucleoside-associated lactic acidosis in HIV- 24:79–84.
infected patients: report of 12 cases and review of the literature. 31. Morgello S, Wolfe D, Godfrey E, Feinstein R, Tagliati M, Simpson
Clin Infect Dis 2002, 34:838–846. DM. Mitochondrial abnormalities in human immunodeficiency
13. May H, Laut F, Palmisano J, Marra A, Marra A, Lewi D, Lanzoni virus-associated myopathy. Acta Neuropathol 1995, 90:
V, et al. Lactic acidosis and antiretroviral therapy: a case report 366–374.
and literature review. Braz J Infect Dis 2000, 4:151–155. 32. Shapshak P, Nagano I, Xin K, Bradley W, McCoy CB, Sun NC,
14. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, et al. HIV-1 heterogeneity and cytokines. Neuropathogenesis.
lactic acidemia and liver dysfunction associated with HIV Adv Exp Med Biol 1995, 373:225–238.
nucleoside analogue therapy: contribution to protease inhibitor- 33. Gherardi R, Florea-Strat A, Fromont G, Poron F, Sabourin J,
related lipodystrophy syndrome. AIDS 2000, 14:F25–F32. Authier J. Cytokine expression in the muscle of HIV-infected
15. Miller KD, Cameron M, Wood LV, Dalakas MC, Kovacs JA. Lactic patients: evidence for interleukin-1alpha accumulation in mito-
acidosis and hepatic steatosis associated with use of stavudine: chondria of AZT fibers. Ann Neurol 1994, 36:752–758.
report of four cases. Ann Int Med 2000, 133:192–196. 34. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B,
16. Mokrzycki MH, Harris C, May H, Laut J, Palmisano J. Lactic Griffin JL. Mitochondrial myopathy caused by long-term zidovu-
acidosis associated with stavudine administration: a report of dine therapy. N Engl J Med 1990, 322:1098–1105.
five cases. Clin Infect Dis 2000, 30:198–200. 35. Simpson D, Katzenstein D, Hughes M, Hammer SM, Williamson
17. Cote H, Brumme B, Craib K, Alexander CS, Wynhoven B, Ting L, DL, Jiang Q, et al. Neuromuscular function in HIV infection:
et al. Changes in mitochondrial DNA as a marker of nucleoside analysis of a placebo-controlled combination antiretroviral trial.
toxicity in HIV-infected patients. N Engl J Med 2002, 346: AIDS 1998, 12:2425–2432.
811–820. 36. Simpson DM, Slasor P, Dafni U, Berger J, Fischl MA, Hall C.
18. Cherry C, Nolan D, James I, Mallal S, McKinnon E, French M, Analysis of myopathy in a placebo-controlled zidovudine trial.
et al. Longitudinal associations between antiretroviral treatments Muscle Nerve 1997, 20:382–385.
and quantification of tissue mitochondrial DNA from ambula- 37. Trojaborg W, Weimer L, Hays A. Electrophysiologic studies in
tory subjects with HIV infection. Tenth Conference on Retro- critical illness associated weakness: myopathy and neuropathy: a
viruses and Opportunistic Infections. Boston, February 2003 reappraisal. Clin Neurophysiol 2001, 1586–1593.
[abstract 133]. 38. Hund E. Neurological complications of sepsis: critical illness
19. Rossi L, Serafini S, Schiavano GF, Casabianca A, Vallanti G, polyneuropathy and myopathy. J Neurol 2001, 248:929–934.
Chiarantini L, et al. Metabolism, mitochondrial uptake and 39. de Letter MA, van Doorn PA, Savelkoul HF, Laman JD, Schmitz
toxicity of 2939-dideoxycytidine. Biochem J 1999, 344:915–920. PI, Op de Coul AA, et al. Critical illness polyneuropathy and
20. Dalakas M, Semino-Mora C, Leon-Monzon M. Mitochondrial myopathy (CIPNM): evidence for local immune activation by
alterations with mitochondrial DNA depetion in the nerves of cytokine-expression in the muscle tissue. J Neuroimmunol 2000,
AIDS patients with peripheral neuropathy induced by 2939 106:206–213.
dideoxycytidine (ddC). Lab Invest 2001, 81:1537–1544. 40. Sander H, Golden M, Danon M. Quadriplegic areflexic ICU
21. Brew B, Tisch S, Law M. Lactate concentrations distinguish illness: selective thick filament loss and normal nerve histology.
between nucleoside neuropathy and HIV neuropathy. AIDS Muscle Nerve 2002, 26:499–505.
2003, 17:1094–1096.
22. Gopinath R, Hutcheon M, Surinder C-D, Halperin M. Chronic
lactic acidosis in a patient with acquired immunodeficiency
syndrome and mitochondrial myopathy: biochemical studies.
J Am Soc Nephrol 1992, 3:1212–1219.
23. Chariot P, Drogou I, de Lacroix-Szmania I, Eliezer-Vanerot B,
Chazaud A, Lombès A, et al. Zidovudine-induced mitochondrial
Appendix
disorder with massive liver steatosis, myopathy, lactic acidosis,
and mitochondrial DNA depletion. J Hepatol 1999, 30:156–160. Members of the HIV Neuromuscular Syndrome Study
24. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie A Group: David Simpson, Lydia Estanislao (Mount Sinai
M, Park Y, et al. Hepatic failure and lactic acidosis due to
fialuridine (FIAU), an investigational nucleoside analogue for Medical Center; New York), Scott Evans, L Li
chronic hepatitis B. N Engl J Med 1995, 333:1099–1105. (Harvard School of Public Health, Boston, Massachu-
25. Semino-Mora C, Leon-Monzon M, Dalakas M. Mitochondrial setts), Justin McArthur, Brendan Lucey (Johns Hopkins
and cellular toxicity induced by fialuridine in human muscle in
vitro. Lab Invest 1997, 76:487–495. University, Baltimore, Maryland), Kendall Marcus,
26. Yiannikas C, McLeod JG, Pollard D, Baverstock J. Peripheral Melissa Truffa (Food and Drug Administration, Rock-
neuropathy associated with mitochondrial myopathy. Ann Neu-
rol 1986, 20:249–257.
ville, Maryland), Robert Naismith, David Clifford
27. Bouillot S, Martin-Negrier M, Vital A, Ferrer X, Laqueny A, (Washington University School of Medicine, St Louis,
Vincent D, et al. Peripheral neuropathy associated with mito- Missouri), J Tyler Lonergan (University of California,
chondrial disorders: 8 cases and review of literature. J Periph
Nerv Syst 2002, 7:213–220.
San Diego, California) Ivan Guerrero, Julio Mendez
28. Mojon D, Kaufmann P, Odel J, Lincoff, NS Marquez-Fernandea (University of Florida, Jacksonville, Florida), Yuwanna
M, Santiesteban R, et al. Clinical course of a cohort in the Cuban Landau (Nassau County Medical Center, Long Island,
epidemic optic and peripheral neuropathy. Neurology 1997,
48:19–22. New York), Marianne Harris, Julio Montaner (BC
29. Cornblath DR, McArthur JC, Kennedy PG, Witte AS, Griffin JW. Centre for Excellence in HIV/AIDS, Vancouver,
Inflammatory demyelinating peripheral neuropathies associated British Columbia), Joseph Gathe, Carl Mayberry
with human T-cell lymphotropic virus type III infection. Ann
Neurol 1987, 21:32–40. (Therapeutic Concepts, Houston, Texas) and Bruce
30. Simpson DM, Bender AN. Human immunodeficiency virus- Cohen (Northwestern University, Chicago, Illinois).
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