|Year : 2022 | Volume
| Issue : 3 | Page : 137-152
Myoclonus associated with infections: A narrative review
Apara Kothiala1, Vijay Shankar2, Soaham Desai3
1 Department of Neurology, GCS Medical College, Ahmedabad, Gujarat, India
2 Apollo Hospital, Chennai, Tamil Nadu, India
3 Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Anand, Gujarat, India
|Date of Submission||05-Jun-2022|
|Date of Decision||23-Oct-2022|
|Date of Acceptance||15-Nov-2022|
|Date of Web Publication||14-Dec-2022|
Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand, Gujarat
Source of Support: None, Conflict of Interest: None
Different movement disorders are reported in association with infectious diseases. In addition, myoclonus can be associated with different types of viral and bacterial infections. We screened three electronic databases for cases of myoclonus as a feature of different infections and collected cases and series describing myoclonus associated with infections. Data regarding study design, sample size, neurological assessment, and diagnostic workup including brain imaging and cerebrospinal fluid analysis were extracted from the identified studies. In this narrative review, we review different infections associated with myoclonus and discuss their salient features. The infections presenting with myoclonus include predominantly subacute sclerosing panencephalitis due to measles. In addition, we describe other viral infections that are reported to associated with myoclonus. Recently, coronavirus disease 2019 infections have been reported to be increasingly associated with myoclonus. The hypothesized mechanisms of infection-related myoclonus are vasculopathy, autoimmune reactions, and inflammation. Although myoclonus is considered to be a result of heredodegenerative, metabolic, or autoimmune disorders, infections may present with myoclonus, especially in tropical and developing countries. In this review, we describe the infections that are associated with myoclonus.
Keywords: COVID-19, movement disorder, myoclonus, prion disease, rubella, subacute sclerosing panencephalitis, tuberculosis
|How to cite this article:|
Kothiala A, Shankar V, Desai S. Myoclonus associated with infections: A narrative review. Ann Mov Disord 2022;5:137-52
|How to cite this URL:|
Kothiala A, Shankar V, Desai S. Myoclonus associated with infections: A narrative review. Ann Mov Disord [serial online] 2022 [cited 2023 Feb 1];5:137-52. Available from: https://www.aomd.in/text.asp?2022/5/3/137/363463
| Introduction|| |
Infectious diseases are common in tropical countries, and their clinical manifestations are observed in various ways. As a result, postinfectious movement disorders (MDs) are common manifestations and are often encountered. Myoclonus is characterized by sudden, brief, shock-like involuntary movements associated with bursts (positive myoclonus) or silencing of muscular activity (negative myoclonus). These movements may occur at rest; during voluntary movements (action-induced); or occur due to provoking sensory, visual, auditory, or emotional stimuli. On the basis of the distribution of jerks, myoclonus can be classified as focal, segmental, axial, multifocal, and generalized. On the basis of the mode of presentation, it is classified as rest, action, and stimulus-induced. On the basis of anatomical source, it can be classified as cortical, cortical-subcortical, subcortical, and segmental. Myoclonus can be a clinical feature of many infectious diseases. It was first described in 1931 during the acute and chronic phases of the encephalitis lethargica epidemic. Myoclonus may present in isolation or along with other clinical features such as opsoclonus and ataxia. In this article, we review cases of isolated myoclonus with infections only. The infections commonly associated with myoclonus are measles, rubella, human immunodeficiency virus (HIV), coronavirus disease 2019 (COVID-19), and prion disease. The various organisms associated with myoclonus are listed below:
Virus: Measles, rubella, HIV, COVID-19, dengue, enterovirus, herpes simplex virus (HSV), West Nile virus (WNV), and John Cunningham (JC) virus
Bacteria: Mycobacterium tuberculosis, Tropheryma whipplei, Treponema pallidum, Streptococcus, Borrelia burgdorferi, Orientia tsutsugamushi, Salmonella typhi, Clostridium tetani, and Legionella
Fungus: Cryptococcus neoformans
Parasite: Plasmodium falciparum
| Methodology|| |
This article is a narrative review study, in which we have attempted to highlight the infections associated with myoclonus. As it is a narrative review, we did not graduate the articles, but we selected the most relevant contributions to this rare presentation of infection-associated myoclonus. A literature search was independently conducted by two reviewers, and all the cases reporting myoclonus in patients with proven central nervous system (CNS) infections were reviewed. We have followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched the PubMed, Embase, and Google Scholar databases for articles on infection-associated myoclonus from January 1, 1965 to March 31, 2022. The literature search strategy was developed using a combination of Medical Subject Heading terms and keywords. The search strings were as follows: myoclonus, infection, virus, encephalitis, subacute sclerosing panencephalitis (SSPE), HIV, acquired immunodeficiency syndrome (AIDS), rubella, Creutzfeldt–Jakob disease (CJD), COVID-19 disease, dengue, enterovirus, HSV, WNV, Lyme disease, Whipple disease, neurosyphilis, scrub typhus, tuberculosis, typhoid, Streptococcus, tetanus, legionella, and Cryptococcus. In addition, we manually searched the reference lists of all articles identified in the electronic search using common search engines (e.g., Google) to include other studies or reports not identified by the search. We excluded case reports and case series of infection-associated opsoclonus–myoclonus–ataxia syndrome, which we plan to review separately. Ethical approval was not required for this study. The search yielded studies that reported myoclonus among patients with different CNS infections. The studies were identified after a detailed search, and data regarding the study design, sample size, neurological assessment, and diagnostic workup including brain imaging and cerebrospinal fluid (CSF) analysis were extracted. After a detailed review of 509 articles and after excluding articles in a non-English language, incomplete details, or contentious or analogous descriptions, a total of 130 articles were included in the final manuscript [Figure 1].
[Table 1] describes the important diagnostic clues, mechanism of myoclonus, and treatment for different infections presenting with myoclonus. Patients with infections may have associated metabolic abnormalities such as hyponatremia, uremia, or hypercapnia, which should be excluded before considering infection-associated myoclonus.
|Table 1: Diagnostic clues, mechanism of myoclonus, and treatment of different infections presenting with myoclonus|
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| Viral infections Leading to Myoclonus|| |
Subacute sclerosing panencephalitis
SSPE is a rare progressive demyelinating disease of the CNS, and it is associated with a chronic infection of the brain tissue caused by mutant measles virus, most commonly observed in children and young adults. The exact global burden of SSPE is unknown. Countries with a high incidence of measles encounter a high incidence of SSPE. India, Pakistan, Papua New Guinea, and Turkey are the countries that have reported majority of the global SSPE cases. The reported incidence rates are 21 cases per million in India, two per million in Turkey, and 0.06 per million in Canada.,, The estimated risk of SSPE among young children (<5 years) affected with measles was 1:1700–1:3300. Widespread immunization has resulted in a >90% reduction in the incidence of SSPE in developed nations. Most patients with SSPE have a history of primary measles infection at an early age (<2 years), which is followed by the onset of progressive neurological disorder after a latent period of 6–8 years. A higher incidence (male:female ratio, 3:1) has been noted in boys.,,
The most common age of onset is 5–15 years, which decreases to usually 5–8 years after measles infection. Myoclonus, cognitive decline, poor scholastic performance, and behavioral abnormalities are the most common presenting features. The disease course may be subacute or gradual downhill, and it can be classified into four stages (Jabbour staging). In stage 1, behavioral changes (such as hypersexuality and inattention) and cognitive decline are observed, leading to poor scholastic performance. Periodic myoclonus heralds the onset of stage 2. The behaviors gradually become frequent and violent, resulting in repeated falls. In stage 3, patients develop combinations of pyramidal and extrapyramidal features such as rigidity, dystonia, tremor, spasticity, and quadriparesis. Stage 4 is characterized by akinetic mutism with autonomic instability manifesting as pyrexia, marked generalized sweating, blood pressure fluctuation, and respiratory rate abnormalities. In such cases, death is unavoidable.
Owing to the predominant subcortical nature of the disease, myoclonus in SSPE is usually slow, periodic, stereotyped, axial, and generalized. Myoclonic jerks initially involve the head and subsequently the trunk and limbs. Muscular contraction is followed by 1–2 seconds of relaxation, associated with a decrease in muscle action potential or complete electrical silence. The myoclonic jerks do not interfere with consciousness. They are exaggerated by excitement and may disappear during sleep. Myoclonus can present as difficulty in gait, periodic dropping of the head, and falling. Subtle myoclonus in the early stages can be made prominent by making the patient stand with their feet close together and arms outstretched in front [see Video 1: Video of myoclonus in a patient with SSPE [Additional file 1]]. The patients are then watched for periodic dropping of the head, neck, trunk, or arms; these are often concomitant with contraction of the facial musculature and slow eye blinks., Generalized myoclonus is more commonly observed than focal myoclonus in such patients.
The exact prevalence of myoclonus in SSPE is not known. Myoclonus may not always be the presenting feature in SSPE, but over the course of the illness, most patients develop myoclonus. Praveen-Kumar et al. observed myoclonus in 93% of the SSPE cases; among these, 71% were generalized myoclonus. Lekhra et al. observed myoclonus in 33.3% of the cases as the second most common presenting feature of SSPE. The most common feature was decreased scholastic performance, which was observed in 58.9% of the cases. Prashanth et al. observed slow myoclonus as the initial feature in 64.1% of the adult-onset SSPE cases; however, during the course of the illness, all patients developed myoclonus involving the limbs and axial musculature. Khadilkar et al. observed that 40.6% of the cases presented with vision loss, behavioral change, and seizures, and the patients developed myoclonus after a mean period of 8 months. Although a diagnostic challenge, when myoclonus is subtle or absent, atypical cases are not infrequent.
Seizures are common in SSPE patients. They can either be focal due to the localized nature of the brain lesions in early diseases or generalized due to the widespread nature of the lesions in advanced diseases., Saha et al. noted myoclonic seizures in 80% and generalized seizures in 18% of the cases. Jagtap et al. observed seizures in 23.5% of the cases, among which myoclonic seizures were most common. Visual involvement can be present in as many as 50% of the patients. Neuroretinitis, chorioretinitis, papillitis, papilloedema, and optic atrophy are among the common ophthalmoscopic findings. Cortical blindness can occur in SSPE due to its predilection for the involvement of parieto-occipital cortex.
The diagnosis of SSPE can be established by Dyken’s criteria, if the patient fulfils any three of the following five criteria: [i] typical clinical presentation with progressive intellectual deterioration with signs of myoclonus; [ii] characteristic electroencephalogram (EEG) findings of periodic, long interval, generalized, symmetrical, and bilateral synchronous high-amplitude slow waves, also known as “Radermecker” complexes, which have a constant relation to myoclonus [see [Figure 2]]; [iii] CSF globulin levels >20% of the total CSF protein; [iv] elevated antimeasles antibody titres in CSF ≥1:4 or ratio ≥1:256 in serum; and [v] brain biopsy showing typical histopathological findings, such as inflammatory changes in the meninges and brain parenchyma, necrotising leucoencephalitis with diffuse demyelination, viral inclusion bodies in the neurons, and neuronal loss.
Magnetic resonance imaging (MRI) findings in SSPE patients are not specific and may be normal in the early stages. In the early stages, parietooccipital and frontal involvement are more common. The involvement of the thalamus, basal ganglia, and the corpus callosum is observed in a remarkable number of patients, while the cerebellum and brainstem are rarely involved. In advanced stages, there is progressive loss of cortical volume, leading to cerebral atrophy. Studies have shown that diffusion tensor imaging is abnormal, even when conventional MRI shows no abnormality. Magnetic resonance spectroscopy demonstrates low N-acetyl aspartate and elevated myoinositol magnetic resonance spectroscopy values.
The electrophysiological basis of myoclonus remains debatable. The temporal relationship of periodic complexes (PCs) with myoclonus suggests a cortical origin. An experimental study has shown that myoclonus can be due to degeneration of the cortical neurons rather than an inflammatory reaction. The alternative hypothesis suggests a deep thalamic or mesencephalic reticular origin with relative cortical integrity or disturbances in the corticosubcortical electrical interaction due to the involvement of both grey and white matter structures. Oga et al. proposed sensorimotor integration as the mechanism of this periodic phenomenon. In a study with magnetoencephalography–EEG localization, the major source location at onset was in the thalami and/or insula. The maximum propensity for being propagated to the ipsilateral cortical structures (viz. pericentral and frontal cortex) and later through the transcallosal pathways to the contralateral hemisphere was observed. In addition, they observed that there are multiple generators for PCs in SSPE. In SSPE, the temporal and spatial relationship between the central PCs and peripheral myoclonus is constant and was found to have simultaneous onset or precede the electromyography discharge. Ser et al. observed an association between subtypes of myoclonus and clinical staging in SSPE. They suggested that myoclonus in SSPE may primarily involve the cortex and corticosubcortical structures, such as the thalamus, at early stages of the disease and involve more caudal structures as the disease progresses.
There is no cure for SSPE. Many drugs have been suggested to stabilize the course of the disease and retard its progression; however, no evidence is available from double-blind randomized clinical trials to date.
Isoprinosine is given orally at a dose of 100 mg/kg (maximum of 3000 mg) per day, usually divided into three to five doses., Interferon-α is usually subcutaneously administered at a dose of 10 million units/m2 three times a week. In addition, interferon-α is intrathecally administered and via the intraventricular route. Furthermore, interferon-β has an immunomodulatory effect. Parenteral interferon-β treatment is usually combined with oral inosiplex., Ribavirin is considered to have inhibitory properties against RNA viruses. In SSPE, ribavirin has been frequently given through intrathecal or intraventricular administration (40–60 mg/kg/day) in combination with interferon-α and Isoprinosine. The current focus is on research targeting molecular mechanisms, such as fusion inhibitors, and mechanisms hindering viral RNA through adenovirus-delivered small interfering RNA.
Myoclonus in SSPE is particularly resistant to treatment. Clonazepam, levetiracetam, sodium valproate, and carbamazepine are anticonvulsants that have been administered in an attempt to control myoclonic jerks.,,
Rubella is a mild viral illness that usually occurs in children aged between 5 and 14 years; however, it can occur in adults following a more severe clinical course. Rubella virus infections may affect the nervous system in three ways: i) direct invasion, such as in congenital rubella; ii) postrubella acute neuromyeloencephalitis; and iii) progressive subacute panencephalitis, which is a late sequelae of either congenital or postnatal acquired rubella. The annual global incidence of Rubella infections ranged from 13.9 cases per million in 2007 to 1.7 cases per million in 2018 as per an analysis of global epidemiologic surveillance on Rubella. Neurological complications are rare, with reported incidences varying from one in 6000 to one in 24000. It has been suggested that following the initial viremia, persistent virus within the neural tissues reacts with circulating antibodies to produce perivascular inflammatory reactions. Postinfectious encephalitis commences within 1 week of the appearance of maculopapular rashes and are typified by headaches, dizziness, behavioral alterations, generalized or focal seizures, and coma.
Progressive rubella panencephalitis (PRP) is a progressive, debilitating encephalopathy that is uniformly fatal. The disease generally occurs in children aged between 10 and 20 years and presents itself as a decline in motor coordination and mental ability. The major clinical features are progressive dementia, signs of pyramidal and extrapyramidal abnormalities, dysarthria, hyperreflexia, cerebellar dysfunction, and choreiform movements. Myoclonic seizures and other epileptic manifestations may be a part of the clinical observations. Asymmetrical myoclonus involving the face and arms have been reported., Wolinsky et al. observed multifocal myoclonus in patients with PRP. In addition, decreased vision with optic atrophy was observed. The course of the disease is progressive and death results within a period of 1–10 years. Total CSF protein is primarily elevated due to oligoclonal production of IgG antibodies specific to the rubella virus. The disproportionate level of antirubella IgG and IgA in CSF compared to that in serum and the visceral organs strongly suggests an intrathecal synthesis of antirubella virus antibodies. PRP is uniformly fatal, and no interruption strategy exists to date.
The severe acute respiratory syndrome coronavirus 2 was first discovered in Wuhan, China, in December 2019, which reached a pandemic status in March 2020. Neurological manifestations of COVID-19 are headache, anosmia, cerebrovascular disease, encephalopathy, and Guillain–Barré syndrome.
Myoclonus is the most commonly reported MD with COVID-19. A study on new-onset MDs with COVID-19 observed myoclonus in 63.4%, ataxia in 38.7%, action/postural tremor in 10.8%, rigid-akinetic syndrome in 5.38%, oculomotor abnormalities in 20.4%, catatonia in 2.1%, dystonia in 1.1%, chorea in 1.1%, and functional (psychogenic) MDs in 3.2% of the reported COVID-19 cases. Thirty cases of myoclonus were observed in a review by Chan et al.. Myoclonus was multifocal or generalized and had acute onset, usually within 1 month of COVID-19 symptoms. Isolated myoclonus was reported in 46.7% of the cases. The mean age was 65 years and 21.6% were women. The severity of myoclonus varied from being manageable in an outpatient setting to requiring hospitalization. Generalized myoclonus with both positive and negative jerks predominantly involved the facial, trapezius, and sternocleidomastoid muscles and as well as muscles in the upper extremities; it worsened with voluntary movements and markedly augmented with auditory and tactile stimuli.
Its pathophysiology can be attributed to a post- or parainfectious immune-mediated mechanism affecting the brainstem, striatum, and cerebellum, or it could be due to direct neuroinvasion. This type of myoclonus has been hypothesized to originate in the brainstem. Myoclonus in this region is characterized by initial muscle activation in the muscles innervated in the lower brainstem, followed by a sequence of both higher brainstem innervated muscles and muscles innervated further down the spinal cord.,, Electrophysiological data that physiologically classify these myoclonic jerks into cortical, cortical-subcortical, subcortical, spinal, or peripheral categories are scarce. The development of myoclonus can be attributed to hyperexcitability of the brainstem neurons or lack of cerebellar inhibitory output.
In addition, diaphragmatic myoclonus or van Leeuwenhoek’s disease has been observed. This presents as involuntary rapid contractions of the abdominal wall, lasting for few minutes and occurring 10–15 times a day. The movements were not provoked or did not worsen by any position and improved with levetiracetam and clonazepam. The pathophysiological origin of diaphragmatic myoclonus is likely to be subcortical, but a good response to levetiracetam suggests partial involvement of the cortex. Posthypoxic myoclonus or Lance–Adams syndrome has rarely been reported with COVID-19. It is defined as action myoclonus that can occur as generalized, focal, or multifocal., The pathophysiology of Lance–Adams syndrome is poorly understood but possibly originates from subcortical and/or cortical structures. In addition, metabolic abnormalities and medications may contribute to myoclonus.
The treatment consisted of symptomatic management with antiepileptic medications and immunotherapy with corticosteroids, intravenous immune globulin, or plasma exchange.
| Human Immunodeficiency Virus|| |
HIV is considered a global pandemic. Sub-Saharan Africa has the largest HIV burden, followed by Asia. Within Asia, India, China, and Thailand have a high prevalence of HIV. HIV had a predilection to infect the nervous system. Akinetic and hyperkinetic MDs have been reported in 2–3% of the patients with HIV infection. In a large study conducted in 2460 HIV patients, neurological manifestations were observed in 42.8% of the patients and 28 (2.7%) patients had MDs. Among these patients, 14 (50%) presented with parkinsonism, six (21.4%) presented with hemichorea/ hemiballismus, two (7.2%) presented with painful legs and moving toes, one (3.6%) presented with Holmes tremor, one (3.6%) presented with hemidystonia, and four (14.2%) presented with myoclonus. Myoclonus was generalized (cortical) in two and localized (spinal) in two patients. Myoclonus could be secondary to opportunistic infections (toxoplasmosis, tuberculosis, and herpes zoster) or to HIV itself. Nath et al. reported seven cases of AIDS with MDs, out of which two had segmental myoclonus. In an older study of 1086 AIDS patients, seven (1.8%) patients had MDs, out of which only one had spinal myoclonus associated with tuberculous myelopathy. Maher et al. reported three cases of generalized myoclonus associated with AIDS–dementia complex, where myoclonus mainly affected the trunk and proximal muscles. In two cases, it was consistently elicited by sudden auditory stimuli, resembling an exaggerated startle response and was a late feature of the disease. The origin of myoclonus may be subcortical (brainstem), and it is possibly a direct effect of the primary HIV encephalopathy rather than a complicating infection or concurrent drug use. One patient with AIDS presented with arm and shoulder segmental myoclonus preceding the onset of herpes zoster radiculitis, which promptly remitted with antiviral treatment. A hypothesis of a localized viral myelitis involving intercalated neurons and sensory pathways contralateral to the skin eruption was considered. Lubetzki et al. described a single case of axial myoclonus causing flexion of the neck, trunk, and lower extremities, in which no structural lesions were found. In this patient, myoclonus was an early manifestation of CNS HIV infection. Management of MDs in HIV patients includes symptomatic treatment, highly active antiretroviral therapy, and treatment of opportunistic infections.
| Prion Disease Leading to Myoclonus|| |
CJD is a rare neurodegenerative disease caused by prion proteins. It affects approximately one individual per million per year worldwide. It is mainly characterized by rapidly progressive dementia, myoclonus, ataxia, visual disturbances, and extrapyramidal and pyramidal involvement, as well as akinetic mutism. Several MDs including myoclonus, dystonia, choreoathetosis, tremor, hemiballismus, “ill-defined complex,” and atypical parkinsonian syndromes, such as corticobasal degeneration and supranuclear palsy, have been described in a remarkable number of patients with the sporadic, familial, or new variant of CJD (v-CJD). The frequency of MDs increases with disease duration, but they sometimes occur at an early stage and have been described as initial and/or isolated manifestations of the illness. MDs can be consecutive to lesions of various structures, including the striatopallidal complex, mesencephalon, and thalamus.
Myoclonus is the MD most commonly associated with sporadic, familial, and v-CJD. Jerks are focal or generalized and have been reported to occur in 82–100% of the cases during the course of the illness, as well as in majority of the advanced forms regardless of the genotype. Myoclonus develops early in patients with methionine/methionine or methionine/valine at codon 129 of the prion protein gene and with the scrapie variant of prion protein PrPSc type 1., In a study by Chandra et al., 13 out of 15 patients with CJD had myoclonic jerks. Myoclonus was generalized and occurred at a frequency of 1 Hz. Myoclonic jerks may present with rest or action. In addition, it may occur later in the disease with stimulus-induced and pseudo-rhythmic myoclonus. Binelli et al. observed that myoclonus had a heterogeneous presentation, and they categorized myoclonic jerks as periodic, rhythmic, or irregular and noted the presence of negative myoclonus in almost 20% of the patients. Periodic myoclonus occurred every 0.5–2 seconds and was mostly generalized (mainly involving the upper limbs) but asymmetric. It occurred at rest and during active movements. Rhythmic myoclonus consists of recurrent jerks at a low frequency (3–5 Hz) that occurred during mild active movements or during posture maintenance. Periodic sharp-wave complexes were present in 98% of the patients but were time-locked with electromyography bursts only in cases with periodic myoclonus. The physiological mechanism is likely to be cortical or thalamocortical hyperexcitability. Chen et al. illustrated that cortical potentials may or may not lock to myoclonic jerks. They hypothesized that the generators of the myoclonic jerks are located at different cortical and subcortical levels. Shibasaki et al. observed that back-averaging demonstrated a sharp wave or power spectral density over the contralateral hemisphere, preceding the myoclonus by 50–85 milliseconds, which suggests a subcortical origin. Matsunaga et al. described one patient with unusual arrhythmic, action-activated jerks causing brief postural lapses in the bilateral upper and lower extremities. The electrophysiological study was consistent with complex negative myoclonus. Stimulus-sensitive negative myoclonus involved a transcortical reflex mechanism. The cortical origins of negative myoclonus could be in the pre- or postcentral areas. It is speculated that the long-lasting decrease in excitability of the primary sensorimotor cortices after stimulation was related to the occurrence of negative myoclonus.
The following various MRI findings are noted in CJD: hyperintensities in the posterior (pulvinar) and dorsomedial thalamic nuclei, so-called “pulvinar and hockey stick” signs in v-CJD, symmetrical bilateral hyperintense signal changes in the basal ganglia (more in caudate and putamen), and cortical ribboning in sporadic CJD. EEG typically shows 1-Hz spikes or triphasic waves that are symmetrical and synchronous with the normal background in the early stages and becomes altered as the disease advances [see [Figure 3]]. CSF 14-3-3 assay detection improves diagnosis accuracy. There is no curative treatment for CJD, and it is symptomatically treated.
| Other Viruses Leading to Myoclonus|| |
Dengue: Dengue is an acute viral disease transmitted by female mosquitoes mainly from the species Aedes aegypti, and it is highly endemic in many tropical and subtropical areas of the world. The neurological complications due to dengue have an incidence of 2.63–40%.,,, MDs associated with dengue are parkinsonism, dystonia, chorea, myoclonus, and stereotypy. Isolated myoclonus is a rare manifestation of dengue infection. In a study by Kulkarni et al., out of 5821 patients with dengue fever that were observed, 154 (2.64%) had neurological complications and one (0.6%) had myoclonus.
Enterovirus: Enterovirus 71 is one of the main causative pathogens of hand, foot, and mouth disease among the pediatric population, particularly in the Asia–Pacific region. The neurological complications of Enterovirus 71 are as follows: (i) brainstem encephalitis, characterized by myoclonus, tremor, ataxia, and autonomic dysregulation; (ii) aseptic meningitis; (iii) encephalitis; and (iv) acute flaccid paralysis. Myoclonus is observed in 57.1–68% of the Enterovirus 71 cases.,,,,, Myoclonus in Enterovirus 19 associated brainstem encephalitis originates from the brainstem; thus, occurring during wakefulness, deep sleep as well as light sleep. In addition, coxsackie virus B4 encephalitis is rarely associated with myoclonus.
HSV: MDs associated with HSV encephalitis are chorea, ballism, choreoathetosis, and myoclonus; these may be related to brain lesions caused by HSV encephalitis. Persistent myoclonus can rarely be a presenting feature of chronic HSV encephalitis presenting with trunk and limb myoclonus associated with ataxia and brainstem symptoms. Negative myoclonus is rarely reported with HSV. In addition, myoclonus is reported in post HSV encephalitis overlapping autoimmune encephalitis, characterized by seizures, psychosis, dystonia, chorea, orofacial and limb dyskinesias, catatonia, rigidity, and ataxia. Furthermore, myoclonus can be observed in HSV encephalitis complicated by a stroke.
WNV: The neurological manifestations of WNV are observed in <1% of the infections, which include meningitis; encephalitis; acute flaccid paralysis; and MDs such as tremor, opsoclonus–myoclonus, parkinsonism, myoclonus, ataxia, and chorea. Sejvar et al. described 16 patients with WNV infection 8 months after the diagnosis and documented MDs in 15 patients; tremor was the most common phenomenology (tremor, 94%; parkinsonism, 69%; and myoclonus, 31%). Maharaj et al. reported a 60-year-old man with WNV infection who developed late-onset myoclonus of the left arm, face, and neck 8 weeks after the diagnosis of WNV infection. Josekutty et al. reported myoclonus along with meningoencephalitic syndrome, spastic quadriparesis, and hyperreflexia in a 44-year-old man. He was subsequently diagnosed with HIV and WNV infections.
JC virus: Progressive multifocal leukoencephalopathy is a rare demyelinating disease of CNS caused by oligodendroglial destruction due to the JC virus. It usually manifests with focal neurological deficits such as motor weakness, sensory abnormalities, visual disturbances, cognitive impairments, and MDs, with a low incidence of 0–2.6%. Sweeney et al. reported the case of an HIV-positive patient with right-hand athetoid and myoclonic movements and lower limbs action and stimulus-sensitive myoclonus; postmortem examination revealed JC virus infection. Another case of progressive myoclonic ataxia in an AIDS patient with progressive multifocal leukoencephalopathy was published by Fontoura et al. This patient developed ataxia and action and stimulus-sensitive myoclonus; brain MRI revealed bilateral subcortical lesions and thalamic/mesencephalon lesions. The authors assumed that the myoclonus was of cortical origin. Chicea et al. reported the case of a 23-year-old woman with HIV infection who presented with right upper limb myoclonus, which was arrhythmic, stimulus-sensitive, and present in rest but more pronounced during action and when maintaining a posture that disappeared during sleep. The patient’s CSF was positive for JC virus.
| Bacterial Infections Inducing Myoclonus|| |
Lyme disease: It is an infectious disease caused by Borrelia burgdorferi and transmitted by tick bites. The neuropsychiatric manifestations such as meningoradiculitis, cranial neuritis, and mononeuritis multiplex are commonly observed but MDs are rarely reported. Propriospinal myoclonus, brainstem reticular myoclonus, and startle myoclonus along with anterocollis are rare manifestations reported with Lyme disease.,,
Whipple disease: Whipple disease is a rare multisystemic infectious disease caused by the bacterium Tropheryma whippelii. Neurological symptoms can appear in 10–43% of the cases and include meningoencephalitis, encephalopathy, hypersomnia, ophthalmoplegia, and cerebellar ataxia. Abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia, tremor, dystonia, and bruxism) are observed in 10–39% of the cases.,, Myoclonus can present as focal and can progress to segmental in few cases. In addition, palatal myoclonus/tremor and stimulus-sensitive myoclonus have been observed.
Neurosyphilis: Neurosyphilis is defined as any involvement of CNS by the bacterium T. pallidum. The MDs that are rarely reported with neurosyphilis include parkinsonism, myoclonus, cerebellar ataxia, chorea, and dystonia., The myoclonus observed can be generalized, affecting the limbs, proximal muscles, and speech, or it can be stimulus-sensitive unilateral myoclonus., Reflex focal myoclonus has been reported in one case that had a presentation of cortico-basal degeneration.
Scrub typhus: Scrub typhus is caused by Orientia tsutsugamushi infection, the rickettsial organism transmitted through the bites of infected chigger (mite) larvae. Meningitis, encephalitis, cranial nerve paresis, transverse myelitis, and polyneuropathy are well-documented manifestations. Tremor, parkinsonism, and myoclonus have been infrequently reported. Furthermore, subcortical myoclonus at rest (which increased with auditory stimuli), diaphragmatic myoclonus, action myoclonus, and startle responses have been reported.,
Tuberculosis: MDs may occur during the course of tuberculous meningitis, and dystonia, chorea, ballism, myoclonus, and tremor have been reported.,,
In a study conducted by Alarcón et al., 30 of 180 patients with tuberculous meningitis developed MDs. Seven of these patients had chorea, three had dystonia, and 20 had tremor. In addition, one patient with tremor had generalized myoclonus at rest. Ashraf et al. reported a child with pulmonary tuberculosis presenting with segmental myoclonus and ataxia. Brainstem tuberculoma can present with an intractable hiccup.
Typhoid: The CNS manifestations of typhoid are delirium, coma, meningitis, seizures, focal neurological deficit, and parkinsonism. Generalized myoclonus was observed in 0.5% of the cases.,
Streptococcus: MDs as a postinfectious manifestation of group A streptococcal infections have been reported and are believed to occur on an autoimmune basis. Poststreptococcal myoclonus can be generalized, segmental, or multifocal.,
Tetanus: Generalized stimulus-sensitive myoclonus with an enhanced startle reflex and electrophysiological findings of bilateral rostrocaudal activation of the axial and limb muscles after stimulation of single peripheral nerves, suggesting brainstem myoclonus, is reported with tetanus.
Legionnaires’ disease: Neurological abnormalities with Legionnaires’ disease include headache, mental confusion, coma, and seizures. Some patients have retrograde amnesia, hallucinations, slurred speech, chorea, cranial nerve palsies, or ataxia. Generalized myoclonus is extremely rare.
| Fungal Infections Leading to Myoclonus|| |
C. neoformans: CNS C. neoformans infections can cause meningitis, encephalitis, and granulomatous lesions. A patient presenting with dementia, choreoathetoid movements, and generalized myoclonic jerks has been reported.
| Parasitic Infections Leading to Myoclonus|| |
Malaria: Isolated myoclonus has rarely been reported as a complication of malaria caused by Plasmodium falciparum. Geerts et al. observed the development of chaotic myoclonic jerks in an afebrile and conscious patient on the fourth day of treatment with quinine. The myoclonus finally resulted in a generalized tonic-clonic seizure and coma, which resolved without further antimalarial treatment. Schnorf et al. observed two patients with acute onset of fluctuating motor aphasia, severe generalized stimulus-sensitive myoclonus, and postural tremor after recovery from P. falciparum malaria infection.
| Limitations|| |
Our narrative review is based on the information from case reports and case studies in the literature. All the limitations of a narrative review apply to this review. Furthermore, associated clinical features of interest such as comorbid non-neurological conditions associated with neurological symptoms such as cognitive deficiencies associated with myoclonus, quality of life, or long-term disability assessment could not be assessed with specific infections because of nonspecific objective measures, subgroup selection, and evaluation bias in the reviewed published articles. Given the rarity of some of the diseases and the fact that only few case series and case reports are reported, it was difficult to ascertain the exact incidence and prevalence of these disorders in any particular region. These limitations emphasize the need to establish dedicated registries for infection-associated MDs, including myoclonus, worldwide.
| Conclusion|| |
Myoclonus is most commonly associated with SSPE than other CNS infections in tropical countries. The hypothesized mechanisms of postinfectious myoclonus are degeneration of cortical neurons, thalamic or mesencephalic-reticular origin of the infection, and propagation to cortical structures through transcallosal pathways and cortical/thalamocortical hyperexcitability. In most studies, the origin of myoclonus is subcortical. In most cases, myoclonus with an infection suggests a more severe disease. [Figure 4] depicts a flowchart approach to myoclonus associated with infections along with certain clues for specific infections. Symptomatic therapy for the treatment of myoclonus with clonazepam, levetiracetam, and sodium valproate may be considered.
|Figure 4: Flowchart depicting an approach to a patient with myoclonus in the setting of infections and certain clues to specific infections|
Click here to view
We thank Dr Atmaram Bansal, Consultant Neurologist, mentor of Dr Apara Kothiala for the contribution of video of SSPE associate myoclonus.
1. Research project: A. Conception, B. Organization, C. Execution;
2. Statistical analysis: A. Design, B. Execution, C. Review and Critique;
3. Manuscript preparation: A. Writing of the first draft, B. Review and Critique.
A. K.: 1BC, 2AB, 3A;
V. S.: 1AB, 2BC, 3B;
S. D.: 1ABC, 2AC 3B.
Ethical compliance statement
The authors confirm that neither informed patient consent nor the approval of an Institutional Review Board was necessary for this work. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]