NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR INDUCED PERIPHERAL

NEUROPATHY IN A CHILD WITH HIV INFECTION

Susanti Rahmayani, Prastiya Indra Gunawan, Riza Noviandi, Sunny Mariana Samosir

Department of Child Health, Faculty of Medicine, Universitas Airlangga/

Dr.Soetomo Academic General Hospital, Surabaya, Indonesia

OBJECTIVE: Pathophysiology of peripheral neuropathy due to NRTIs agents cause

peripheral nerve damage with various mechanisms like microtubular damage, mitochondrial
dysfunction, and neuronal apoptosis. The aim of this study highlight the importance of early
detection and how to solve the side effect of NRTIs, focus on peripheral neuropathy.

CASE REPORT: We report a 13 years old girl with chief complaint right hand twitching that
was more severe since three days before went to neuropediatric outpatient clinic.
Antiretroviral that she taken at first were lamivudine 30 mg every 12 hours, stavudine 7.2 mg
every 12 hours and nevirapine 60 mg every 24 hours. Neurologic examination showed no
weakness and atrophy in the upper right limb muscles. There was no atrophy in her right and
left hands. Rigid was present at moment when fasciculations happened. She had given
trihexyphenidyl 2 mg every 12 hours and showed progress in three weeks. The
fasciculations significantly decreased.

CONCLUSION: Patient-associated risk factors for NRTI-induced peripheral neuropathy

include prior underlying neuropathy, prior HIV-associated neuropathy, underlying
malignancy, and low CD4 count or immunodeficiency. The diagnosis of NRTIs induced
peripheral neuropathy requires careful clinical assessment from history taking, judicious
laboratory testing, and electrodiagnostic studies or nerve biopsy if the diagnosis remains
unclear. Treatment of peripheral neuropathy has two goals, they are controlling the
underlying disease process and treating troublesome symptoms. NRTIs to this patient
cannot be eliminated, so, symptoms should be decreased. She had been given
trihexyphenidyl 2 mg every 12 hours and showed progress in three weeks. The
fasciculations significantly decreased. This patient have a good prognose because no
complications were found during and after regimen trihexyphenidyl is given.

Keywords: NRTI, Peripheral Neuropathy, HIV Infection, Trihexyphenidyl.

INTRODUCTION

NRTIs associated with peripheral neuropathy include zalcitabine (ddC), didanosine

(ddI), stavudine (d4T), and lamivudine (3TC). The incidence of peripheral neuropathy with
these drugs varies by agent and is a frequent reason cited for discontinuation of antiretroviral
therapy. Up to 10% of patients taking zalcitabine have been reported to stop treatment due
to this side effect. 34% of patients treated with didanosine develop painful peripheral
neuropathy, and 1- 2% stop therapy as a result. In patients treated with stavudine, 49.8% of
patients taking 40 mg b.i.d. developed peripheral neuropathy, and 11.2% taking less than 30
mg twice a day. developed peripheral neuropathy. Lamivudine seems to have a low
incidence of peripheral neuropathy compared to other NRTIs, although the reason for this is
unclear.1,2

Pathophysiology of peripheral neuropathy due to NRTIs agents cause peripheral

nerve damage various mechanisms like microtubular damage, mitochondrial dysfunction,
neuronal apoptosis etc. Damage to the microtubules causes impairment in axonal
transmission and mitochondrial dysfunction. Mitochondria play an essential role in cellular
energy production and calcium homeostasis. Abnormalities in mitochondrial homeostasis
and function are seen in several acquired as well as genetic neuropathies, emphasizing their
prominent role in neuronal cell activities. The mitochondrial dysfunction is due to opening of
mitochondrial permeability transition pore (mPTP), swollen and vacuolated mitochondria
which brings Ca2+ deregulation and activation of caspases thus driving the neuronal cell
towards apoptosis.3,4,5

The diagnosis of NRTIs induced peripheral neuropathy requires careful clinical

assessment from history taking, judicious laboratory testing, and electrodiagnostic studies or
nerve biopsy if the diagnosis remains unclear. According those, the purpose of this paper is
to report a case of NRTIs induced peripheral neuropathy in a child with HIV infection. These
studies highlight the importance of early detection and how to solve the side effect of NRTIs,
focus on peripheral neuropathy.
CASE REPORT

Female 13 years old girl, 53 kg, 145 cm, went to neuoropediatric outpatient clinic with
chief complaint right hand twitching that was more severe since three days before went to
neuropediatric outpatient clinic. In a day, the right hand twitches more than once, most at the
thumb and index finger, which in a day can occur more than five times with a twitch duration
of about one to three minutes and there was no pain when twitching happens. But, lately it
happens also in left hand, but not frequently. No fever, no vomiting, no seizure at that time.
Patient was diagnosed with HIV since 2009.
Antiretroviral that she taken at first were lamivudine 30 mg every 12 hours, stavudine
7.2 mg every 12 hours and nevirapine 60 mg every 24 hours. So, she’s been taking
antiretroviral for 12 years. Now, the antiretroviral (ARVc) combination that she taken are
lamivudine 150 mg, zidovudine 300 mg and nevirapine 200 mg, all every 12 hours and as
known as full doses. She’s been taking this full doses since her weight 30 kg at 7 years old.
There was found fasciculation at right index finger and right thumb, no pain, of about
three minutes. The symptoms were initially located along the distal portion of the right arm,
with no subsequent progression to the entire arm. Neurologic examination showed no
weakness and atrophy in the upper right limb muscles. There was no atrophy in her right and
left hands. Rigid was present at moment when fasciculations happen. Nevertheless, muscle
power also was normal in the lower limbs. Deep tendon reflexes were considered normal in
all four limbs. Superficial and deep sensibilities were normal, as well as those of cranial
nerve. There were no fasciculations or atrophy in the tongue.
The patient was diagnosed with suspicious Nucleotide Reverse Transcriptase
Inhibitors (NRTIs) induced peripheral neuropathy from last findings. There was diagnostic
plan to give motor and sensory conduction studies, EMG upper and lower limbs for ensuring
the diagnose. She had given trihexyphenidyl 2 mg every 12 hours and showed progress in
three weeks. The fasciculations significantly decreased.

DISCUSSION

A girl, 13 years old, had been taken combination antiretroviral for 12 years with
fasciculations in upper limb, especially in the right thumb and index finger, happen of one to
three minutes without any weakness. Lately, it also happens in the left hand, but not often.
Rigid was performed at moment when fasciculations happen. Peripheral neuropathy has a
variety of systemic, metabolic, and toxic causes. The most common treatable causes include
diabetes mellitus, hyperthyroidism, and nutritional deficiencies.1 Certain medications have
been implicated in the iatrogenic development of drug induced peripheral neuropathy (DIPN)
include chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic,
anticonvulsants, NRTIs and among others. This case report will explain concepts regarding
the mechanism, common inciting medications, and treatment options for drug-induced
peripheral neuropathy. Drug-Induced Peripheral Neuropathy (DIPN) occurs when a chemical
substance causes damage to the peripheral nervous system.1,6 Fasciculation and
paraesthesia are symptoms inluded of peripheral neuropathy. Before any further treatments
are evaluated, differential diagnosis of peripheral neuropathy condition should be ruled out,
comorbidities should be treated, persistent triggers should be eliminated, and patient
adherence should be optimized, which still possible to diagnose many others with presenting
peripheral neuropathy condition.

Figure 1. Fasciculation at Right Thumb

The neuropathy associated with NRTIs use is primarily peripheral, likely due to the fact
that peripheral nerves have a leakier blood-nerve barrier compared to central neurons,
possibly making them more susceptible than central neurons to damage by NRTIs. NRTIs
cause a distal axonal-type sensory neuropathy that can be similar to and difficult to
distinguish from primary HIV-induced neuropathy. It often manifests clinically as burning,
shooting pain, paraesthesia, twitching, distal weakness, and a decreased ankle jerk reflex.
Electromyography (EMG ) studies on patients with NRTI-induced peripheral neuropathy
show a decreased action potential amplitude with a normal latency, which is a pattern
commonly seen in axonal. 7,8,9
 Figure 2. Fasciculation at Right Index Finger

The diagnosis of NRTIs induced peripheral neuropathy requires careful clinical

assessment from history taking, judicious laboratory testing, and electrodiagnostic studies or
nerve biopsy if the diagnosis remains unclear. A systematic approach begins with
localization of the lession to the peripheral nerves, identification of the underlying etiology,
and exclusion of potentially treatable causes. Initial blood tests should include a complete
blood count, comprehensive metabolic profile, and measurement of erythrocyte
sedimentation rate and fasting blood glucose, vitamin B12, and thyroid-stimulating hormone
levels; specialized tests should be ordered if clinically indicated to exlude differential
diagnose.10 Electrodiagnostic studies, including nerve conduction studies and
electromyography, can help in the differentiation of axonal versus demyelinating or mixed
neuropathy as generally been considered the gold standard for diagnostic testing in
peripheral neuropathy.10,11,12

Treatment of peripheral neuropathy has two goals, they are controlling the underlying
disease process and treating troublesome symptoms. 13 The former is usually achieved by
eliminating offending agents. Most commonly, DIPN presents with only mild sensory
paraesthesias and does not warrant any specific intervention other than a possible reduction
or cessation of the specific agent causing neuropathy. However, when the neuropathy
causes significant disability or pain several treatment options are available to help reduce
the DIPN and subsequent pain. Current management includes Tricyclic Antidepressants
(TCAs), serotonin and noradrenalin reuptake inhibitors (SSRIs and SNRIs), gabapentinoids,
and other interventional modalities.14

This patient is given trihexylphenidil 2 mg twice a day. For this almost a month, the
fasciculations decreased significantly, without any symptomatic side effect. Trihexyphenidyl
and other anticholinergic drugs can solve this disorder by reducing the neurotransmission
mediated by acetylcholine. In studies using experimental animals, trihexyphenidyl showed a
stimulating effect of dopamine production on the striatum, through the blockade of
muscarinic receptors on the parasympathetic nervous system. The blockade of muscarinic
receptors results in the release of acetylcholine followed by dopamine production. At
dystonia, dopamine production is relatively low, so stimulation of dopamine production by
trihexyphenidyl is thought to reduce symptoms.15 This patient have a good prognose
because in this patient no complications were found during and after regimen
trihexyphenidyl.

CONCLUSION

This patient has been taking ARV combination, included NRTIs group for 12 years.
Lately, she went to neuoropediatric outpatient clinic with chief complaint right hand twitcing
that was more severe since three days before went to neuropediatric outpatient clinic. In a
day, the right hand twitches more than once, most at the thumb and index finger, which in a
day can occur more than five times with a twitch duration of about one to three minutes and
there was no pain when twitching happens. From history taking, physical examination,
laboratory examination pointed to suspicious NRTIs induced peripheral neuropathy.

Treatment of peripheral neuropathy has two goals, they are controlling the underlying
disease process and treating troublesome symptoms. NRTIs to this patient can not be
eliminated, so, symptoms should be decreased. She had given trihexyphenidyl 2 mg every
12 hours and showed progress in this three weeks. The fasciculations significantly
decreased. This patient have a good prognose because no complications were found during
and after regimen trihexyphenidyl is given.

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