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| REVIEW ARTICLES |
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| Year : 2020 | Volume
: 3
| Issue : 3 | Page : 129-144 |
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Neurosyphilis-associated movement disorder: A literature review
Jamir Pitton Rissardo, Ana Letícia Fornari Caprara
Medicine Department, Federal University of Santa Maria, Santa Maria, Brazil
| Date of Submission | 21-Apr-2020 |
| Date of Decision | 31-May-2020 |
| Date of Acceptance | 01-Jul-2020 |
| Date of Web Publication | 07-Nov-2020 |
Correspondence Address:
Dr. Jamir Pitton Rissardo
Rua Roraima, Santa Maria, Rio Grande do Sul.
Brazil
 Source of Support: None, Conflict of Interest: None  | 4 |
DOI: 10.4103/AOMD.AOMD_21_20
Syphilis is a well-known “great simulator/mimicker” of other diseases. Over the last decades, the clinical features of neurosyphilis have changed with an increasing percentage of atypical manifestations. In this context, movement disorders caused by neurosyphilis are rare and challenging to diagnose. This literature review aimed to evaluate the clinical epidemiological profile, pathological mechanisms, and historical features of neurosyphilis-associated movement disorders. Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 84 reports containing 168 cases who developed a movement disorder related to neurosyphilis were reported. The mean and the median reported ages were 40.50 (standard deviation [SD], 20.30) and 43 years (2.5–72.5 years). The predominant sex was male (79.16%). Argyll Robertson pupils were found in 54.90% of the individuals. The movement disorders reported were tremor, chorea, parkinsonism, ataxia, myoclonus, dystonia, athetosis, and ballism. In the literature, we have a large number of reports about movement disorder associated with neurosyphilis. But, in the majority of them, the individuals had the syphilitic diagnosis based on unspecific methods, electrodiagnostic studies were not performed, or penicillin therapy was unavailable. Also, we believe that any patient presenting with a movement disorder should have a thorough neurological examination of pupillary reflex, and if any abnormality is present, syphilitic laboratorial tests should be done. Keywords: Literature review, movement disorder, neurosyphilis, parkinsonism, syphilis
How to cite this article:
Pitton Rissardo J, Fornari Caprara AL. Neurosyphilis-associated movement disorder: A literature review. Ann Mov Disord 2020;3:129-44 |
How to cite this URL:
Pitton Rissardo J, Fornari Caprara AL. Neurosyphilis-associated movement disorder: A literature review. Ann Mov Disord [serial online] 2020 [cited 2023 May 30];3:129-44. Available from: https://www.aomd.in/text.asp?2020/3/3/129/300256 |
| Key messages | |  |
1. Syphilis is a disease caused by the spirochete Treponema pallidum  d is a well-known “great simulator/mimicker” of other diseases.
2. Most of the experience with movement disorders in syphilis comes from older literature, the resurgence of the disease per se can justify a review of initial and more recent reports.
3. Candy sign is possibly a pathognomonic sign of neurosyphilis. It reproduces a movement performed in normal life (candy sucking) without any additional feature; it is a slow and intermittent muscle contraction.
| Introduction—Syphilis the “Great Mimicker” | | |
Syphilis is a disease caused by the spirochete Treponema pallidum. The clinical manifestations of this infectious disease are classified into four stages: primary syphilis, secondary syphilis (early-latent syphilis and late-latent syphilis), and tertiary syphilis. Approximately 2–12 weeks after the exposure to the T. pallidum, the individual can develop primary syphilis, which is characterized by a chancre that disappears within 2–6 weeks. If the disease is untreated, a secondary stage can occur within 4–10 weeks from the onset of the first painless sore. The clinical symptoms of secondary syphilis include maculopapular rash, fever, and regional lymphadenopathy. In the tertiary stage, the spirochete can spread to the central nervous system, or the lymphatic, cardiovascular, and musculoskeletal systems [Figure 1].[1],[2] The lyrics of “Luetic Lament” by Isaac Asimov (American writer and professor of biochemistry at Boston University) humorously describe the natural history of syphilitic infection in an immunocompetent host. It is believed that although this limerick was attributed to him, it was probably done by an anonymous American physician in the 1920s.[3]
Historically, at the end of the fifteenth century, syphilis was imported from the New World to Europe, spreading to the rest of the world and becoming ubiquitous by the end of the eighteenth century.[4] During the nineteenth century, syphilis affected an important part of the population, and many reports of patients with signs and symptoms of congenital syphilis associated with neurological manifestations raised the idea of possible infection of the central nervous system by this pathogen.[5] Also, the knowledge about the T. pallidum was poor at that time, so several hypotheses and classifications tried to elucidate the pathophysiological mechanisms, localization of lesions, risk factors, and clinical manifestations of neurosyphilis. For example, Gowers[6] dived the symptomatology of neurosyphilis into two classes: neuroses and adneural diseases. The first was described as direct infection of T. pallidum to the nerve cells or fibers. On the contrary, the second occurred due to abnormalities in the tissues that protect, support, or convey blood to and from the nerve structures. This division was interesting because it was one of the first attempts to correlate the pathological mechanisms of syphilis neuroinvasion with clinical symptoms.
Although the incidence of neurosyphilis has decreased after the advent of penicillin (because syphilis is generally resolved before the appearance of central nervous system involvement), it is still a common disease in developing countries.[2] So, general practitioners should be able to recognize the different clinical presentations of neurosyphilis and effective forms of treatment. The typical forms of neurosyphilis that are widely recognized are tabes dorsalis (progressive locomotor ataxia) and general paresis (general paresis of the insane, dementia paralytica, Lissauer form).[7]
Syphilis is a well-known “great simulator/mimicker” of other diseases.[4] Over the last decades, the clinical features of neurosyphilis have changed with an increasing percentage of atypical manifestation due to unknown causes.[1] Some authors stated that “the typical presentation of neurosyphilis is now the atypical forms.”[8] In this context, movement disorders, other than sensory ataxia, caused by neurosyphilis are rare and challenging to diagnose. It is noteworthy that most of the experience with movement disorders in syphilis comes from older literature, but the resurgence of the disease may justify a review of initial and more recent reports.
Tong et al.[9] investigated the spectrum of movement disorders secondary to neurosyphilis in more than 100 individuals. Only seven individuals presented an abnormal movement, which included four patients with Parkinsonism More Details, one with laryngeal dystonia, one with a corticobasal syndrome, and one with sensory ataxia. Shah and Lang[10] reviewed the literature on acquired neurosyphilis presenting as a movement disorder, in which they found twenty-one articles. This literature review aimed to evaluate the clinical epidemiological profile, pathological mechanisms, and historical features of neurosyphilis-associated movement disorders.
| Methods | | |
Search strategy
We searched six databases in an attempt to locate all of the reports about movement disorders associated with neurosyphilis published until 2019 in electronic form. Excerpta Medica (Embase), Google Scholar, Latin American, and Caribbean Health Sciences Literature (Lilacs), MEDLINE, Scientific Electronic Library Online (SciELO), and ScienceDirect were searched. Search terms were “parkinsonism, tic, dyskinesia, dystonia, stuttering, myoclonus, restless legs syndrome, akathisia, tremor, chorea, restlessness, ataxia, ballism, hyperkinetic, hypokinetic, bradykinesia, and movement disorder.” These terms were combined with “syphilis, neurosyphilis” [Supplementary Table 1]. | Supplementary Table 1: Free text and MeSH search terms in the US National Library of Medicine
Click here to view |
Inclusion and exclusion criteria
Case reports, case series, original articles, letters to the editor, bulletins, and poster presentations published until 2019, were included in this review with no language restriction. The two authors independently screened the titles and abstracts of all papers found in the initial search. Disagreements between the authors were resolved through discussion.
Cases where the cause of MD was already known and the motor symptoms were not worsened or were not related to neurosyphilis were excluded. Also, cases that were not accessible by electronic methods, including after a formal request e-mailed to the authors, were excluded.
Data extraction
A total of 2533 papers were found; 2449 articles did not meet the inclusion criteria [Figure 2]. When provided, we extracted movement disorder type, authors, department, year of publication, country of occurrence, number of patients affected, age, sex, presence of Argyll Robertson pupil, cerebrospinal fluid analysis, neuroimaging features, patient’s status at follow-up, and important findings of clinical history and management. The data were extracted by two independent authors, double-checked to ensure matching, and organized by whether or not the movement disorder was caused by neurosyphilis.
Statistical analysis
Categorical variables were represented as proportions; continuous variables were represented as mean, standard deviations, median, and range.
Definitions
The clinical characteristics and definitions of the movement disorders, such as dystonia, restless legs syndrome, akathisia, dyskinesia, tremor, parkinsonism, tic, chorea, ballism, and myoclonus, were obtained from the reference article by Jankovic and Tolosa.[11] In the cases where the non-English literature was beyond the authors’ proficiency (English, Portuguese, Spanish, Italian, French, and German) and the English abstract did not provide enough data, then Japanese, Chinese, Russian, and Dutch Google Translate service were used.[12]
| General Data | | |
A total of 84 studies containing 168 cases who developed a movement disorder secondary to neurosyphilis were reported [Table 1].[5],[9],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94] The mean and the median reported ages were 40.50 (standard deviation [SD], 20.30) and 43 years (2.5–72.5 years). The predominant sex was the male (79.16%, 76 of 96). | Table 1: Literature review of neurosyphilis-associated movement disorder
Click here to view |
Argyll Robertson pupils are bilateral small pupils that react to accommodation but not to light. They are usually seen in parenchymatous neurosyphilis associated often with tabes dorsalis, in which the responsible lesion is localized in the midbrain tectum proximal to the oculomotor nuclei.[3] This finding was noted in neurosyphilis-associated movement disorder at 54.90% (28 of 51). Hence, we believe that any patient presenting with a movement disorder should have a neurological examination of pupillary reflex, and if an abnormality is present, syphilitic laboratorial tests should be done.[95]
[Table 2] is a visual representation of the number of reports about neurosyphilis-associated movement disorder. In 2012, Shah and Lang[10] published a literature review about acquired neurosyphilis presenting as a movement disorder, in which they only found 21 articles. The methodological differences of their review to this study are that we included articles without language restriction, and from other databases rather than only MEDLINE or PubMed. In this way, we encountered different results such as the prevalence of each movement disorder with the most commonly reported being tremors, followed by chorea and parkinsonism. | Table 2: Number of reports of neurosyphilis-associated movement disorder
Click here to view |
| Chorea—Jackson, Morse, and the “Candy Sign” | | |
The first descriptions of a movement disorder related to syphilis were probably with chorea, or at least a large number of reports associated with choreiform movements were published in the pre-penicillin era. In our review, we found the commentaries of J. Hughlings Jackson (1835–1911), an English neurologist, about a case where he observed a girl who had hemichorea and congenital syphilis.[5] But we believe that this could not be classified as the first report in the literature presenting this hypothesis because of two reasons. The first is that this review was based on the electronic form, and many important studies about syphilis are still present only in hard copies. Second, his discussion leads to a possible understanding that other authors had already proposed this association.
The link between chorea and neurosyphilis was hypothesized by English authors and later was supported by French specialists. They observed that some pediatric patients with acute or subacute chorea had an important syphilitic history since they had congenital syphilis or their parents had signs of syphilis.[16] Some French authors, to support their hypothesis, even treated all cases of chorea with salvarsan or neosalvarsan.[96] It is worthy of mentioning that these syphilitic diagnoses were done with Wassermann reaction, which is an antibody test for syphilis based on complement fixation, that is not specific to syphilis and can have a positive reaction to other diseases such as systemic lupus erythematosus, malaria, and tuberculosis.[2] Therefore, the syphilitic diagnosis was possibly a coincidental co-occurrence of the infection with chorea. Moreover, the patients did not use specific antisyphilitic therapy such as penicillin, and they did not have long-term follow-up.
Morse and Floyd[97] investigating the association of chorea and syphilis concluded that syphilis plays no direct part in the etiology of chorea. In addition, they found that these choreic individuals had a history of pharyngitis and sometimes associated with “rheumatism” and endocarditis. Their study was one of the first to describe a probable microorganism from tonsils and/or teeth causing chorea, which was further discovered as being the Group A beta-hemolytic Streptococcus.[98]
Orolingual dyskinesia sometimes also classified as orofacial chorea by some authors was commonly noted in syphilitic patients. Camillo Negro (1861–1927), an Italian neurologist and neuropathologist, first reported this association in 1913, postulated this sign as being pathognomonic of neurosyphilis, and called it “candy sign.”[99] Later, other authors described this phenomenology as “dysarthria and tremor prevailing in the labiolingual region,”[100] “facial, lingual, and hand tremor,”[101] “twitching of the face and tongue resulting in dysarthria and buccolingual masticatory movements,”[102] “facial grimacing,”[59] “trombone tremor of the tongue,”[103] or “trombone tongue.”[69] Martinelli et al.[69] defined “candy sign” as a sign different from previous descriptions because it reproduces a movement performed in normal life (candy sucking) without any additional feature; it is not a tremor (oscillatory movement around an axis) nor a sudden movement, but a slow and intermittent muscle contraction. [Table 3] is a summary of neurosyphilis-associated tongue movement disorders.[69],[73],[81],[82],[93],[99],[104],[105]
Blakeley and Jankovic[55] studied the characteristics of secondary paroxysmal dyskinesias in 17 individuals. They observed that only meningovascular syphilis has chorea as the most common clinical manifestation, whereas other causes of secondary paroxysmal dyskinesias (stroke, trauma, and multiple sclerosis) have dystonia as the main movement disorder. These findings were interesting because even without preliminary results and only based on a detailed neurological examination, the etiological diagnosis of a patient presenting with subacute paroxysmal dyskinesias can be assumed.
| Parkinsonism—Loeper, Mella, and Adolf Hitler | | |
After many years of only studying the relation between syphilis and chorea, some neurologists started assessing the influence of syphilis in other neurological diseases. In the early twentieth century, neurological diseases were thought to be caused by unknown microorganisms.[94] In this context, patients diagnosed with Parkinson’s disease were being investigated with syphilitic tests, and many of them had positive results.[18] Important drawbacks of these studies were that almost all patients were elderly, and the tests had still low specificity to syphilis. We believe that as well as with chorea, the first descriptions were only coincidental. This same idea was shared by Kinnear Wilson[106] almost 30 years later of the first reports, in the penicillin era. Besides, it is relevant that part of the individuals who developed severe forms of neurosyphilis had significant cognitive impairment and general paresis of the insane. Therefore, their abnormal movements, especially the bradykinesia, could have been caused by a poor cognitive function due to the clinical syphilitic form, which was probably a confounding variable between the neurosyphilis and parkinsonism.[107]
Loeper was probably the first to report pathological changes in the caudate nucleus due to a syphilitic lesion leading to parkinsonism.[108] He observed a large number of obliterated blood vessels with small hemorrhages in the parenchyma some of which were organized, indicating a chronic process. Mella and Katz[18] reported an autopsy of a parkinsonian individual diagnosed with syphilis, which showed microscopical lesions in the striatal structures such as perivascular infiltration of round and rod cells in the pallidum, and nerve cell degeneration. Both studies of Loeper and Mella and Katz, even though presented pathological findings of both syphilis and Parkinson’s disease, were important because they showed localized lesions in the striatum. In the same period, Wilson and Cobb[20] reported four individuals that had parkinsonism and syphilis, and they noted lesions in the midbrain in the gross neuroanatomy, which they called parkinsonism by syphilitic mesencephalitis.
The cases reported showed a wide spectrum of clinical presentations such as akinetic-rigidity parkinsonism, tremor-dominant parkinsonism, progressive supranuclear palsy-like syndrome,[51] and corticobasal syndrome.[57] The majority of the reports did not clearly describe the follow-up and outcomes of the patients after the treatment. Almost all these reports showed poor prognosis. In the penicillin era, at least three cases had a complete recovery of motor symptoms.[49],[79],[80]
An interesting historical fact about the association of parkinsonism and neurosyphilis is the history of Adolf Hitler. It is believed that he had irritable bowel syndrome, skin lesions, cardiac dysrhythmia, coronary arterial disease, syphilis, borderline personality disorder, amphetamine addiction, and parkinsonism.[109] We believed that his parkinsonism, psychological disorders, and cardiac abnormalities could be explained by syphilis. Many researchers hypothesized that he had syphilis when he was a younger adult, and his parkinsonism was observed later in life and worsened throughout the Second World War.[110] It is possible that due to untreated syphilis in the pre-penicillin era, he developed neurosyphilis throughout the years, which might have damaged the striatum, causing parkinsonism. Nevertheless, this can only be supposed because of the lack of objective evidence, and the fact that some historians doubt that he had syphilis or even parkinsonism.[111]
| Myoclonus—Intention Tremor × Action Myoclonus | | |
In the majority of the reports of syphilitic patients with myoclonus, the individuals had cognitive impairment. The presence of myoclonus associated with dementia has a limited range of differential diagnosis, in which the most common conditions are Creutzfeldt–Jakob disease, Alzheimer’s disease, corticobasal syndrome, Hashimoto’s encephalitis, and paraneoplastic syndromes.[112] In this way, neurosyphilis should be investigated in patients presenting this association.
Okuma et al.[54] reported an elderly male presenting with action myoclonus secondary to syphilis. They observed that their patient probably had cortical reflex myoclonus because jerk-locked back averaging was present without sensory-evoked potential being enlarged. Interestingly, patients with neurosyphilis presenting with tremor may have action myoclonus instead of intention tremor, but only detailed electrodiagnostic studies can differentiate these conditions.[113],[114] Therefore, electrophysiological studies are suggested to be performed in any syphilitic patient presenting with tremor.
One important fact about the patients that presented myoclonus is that the majority also had general paresis, which is characterized by Argyll Robertson pupils, dementia, psychosis, and hyperreflexia.[3] The presence of Argyll Robertson pupils can partially explain the subcortical source of the myoclonus.[112] But, the majority of the studies did not perform electrodiagnostic studies, so the cortical source cannot be excluded. Besides, some authors reported “jerks” in the electroencephalogram.[47] The myoclonus types found were focal, segmental, multifocal, and generalized.
| Ataxia—Tabes Dorsalis, Sensory, and Cerebellar | | |
Ataxia is a common sign among patients with syphilis. It is noteworthy that ataxia can be divided into cerebellar and sensory. The sensory ataxia is by far the most common encountered in neurosyphilis due to lesions in the spinal cord. This late manifestation of neurosyphilis is known as tabes dorsalis and is characterized by slow demyelination of the neural tracts primarily in the dorsal root ganglia.[115] Thus, the clinical features of tabes dorsalis include sensory ataxia, lightning-like leg pain, bowel/bladder dysfunction, and Charcot’s joints. Duchenne[116] was probably the first to describe sensory ataxia in a patient with syphilis, but the association between T. pallidum and tabes dorsalis was done only after the studies of Charcot and other authors.[10]
On the contrary, the cerebellar ataxia was rarely reported with syphilis. [Table 4] shows the division of the cerebellar ataxias according to their etiology such as meningovascular, meningomyelitis, and mixed (vascular and parenchymal neuroinvasion).[28],[45],[58],[61],[67],[79],[87],[92] We can highlight important facts based on this table. First, the majority of the cases had a meningovascular involvement of the cerebellar arteries, leading to localized infarction of the cerebellar region. Second, we can observe that those individuals who did not present isolated meningovascular syphilis had a vascular episode associated with parenchymal tissue causing symptoms of general paresis.[87] Third, the individuals had acute and subacute cerebellar syndromes. The differential diagnosis of acute cases was cardioembolic sources, and of subacute cases were metabolic conditions such as vitamin B12 deficiency and immune-mediated diseases.[87],[92] | Table 4: Cases of neurosyphilis presenting with cerebellar ataxic syndrome
Click here to view |
Ai-Yong et al.[90] investigated the clinical features of individuals presenting with ataxia secondary to neurosyphilis. The neurosyphilis group, when compared to the cerebral infarction group, showed the worst cognitive impairment and poor gait performance. They stated that for patients presenting with ataxia associated with any mental/cognitive disorder and poor performance in static gait, neurosyphilis should be considered.
| Dystonia, Ballism, Athetosis–Laryngeal dystonia, Laryngitis | | |
Chauhan and Pickens[64] reported a case of an adult female presenting with recurrent opisthotonus episodes. Their study reinforces the hypothesis of neuroinflammatory pathogenesis by T. pallidum, leading to an abnormal striatal organization. This could be supported by the pathological explanation of opisthotonus that is believed to occur due to a relative imbalance between the inhibitory and facilitatory neurologic pathways serving the involved muscle groups.[117]
Laryngeal dystonia associated with neurosyphilis was anecdotally reported, which is interesting because, in its early stage, syphilis can cause laryngitis characterized by aphonia.[118] Also, the lesions in the laryngeal dystonia are probably in the central nervous system, mainly in the basal ganglia, but the cause of laryngitis is painless laryngeal lesions.[119] Ho et al.[63] reported a case of laryngeal dystonia, in which the brain magnetic resonance imaging revealed generalized atrophy and infarcts in multiple vascular territories, including the basal ganglia. Thus, the lesion in the striatal region possibly led to an overactivation of the direct pathway as well as other conditions already reported.[120] Another interesting finding of their study was the fact that botulinum toxin injections to each thyroarytenoid muscle showed marked improvement of the patient’s voice quality.
Dooling and Adams[39] studied the pathological anatomy in individuals with post-hemiplegic athetosis. One of their reports was about a middle-aged man that had athetosis, and the diagnosis was a cavitating lesion of the lenticular and caudate nuclei caused by occlusion of the lenticulostriate branches of the middle cerebral artery by meningovascular syphilis. They had this conclusion based on positive syphilitic laboratorial tests, gliosis of the putamen associated with inflammatory infiltrate in the surrounding, and abnormalities in the arterial branches.
| Conclusion | | |
In summary, movement disorders associated with neurosyphilis were widely reported in the literature. The most commonly described were tremors, followed by chorea and parkinsonism. But, in the majority of the reports, the individuals had the syphilitic diagnosis based on unspecific methods, electrodiagnostic studies were not performed, or penicillin therapy was unavailable. Therefore, further studies need to perform tests more specific to syphilis and reevaluate the patients in the long-term follow-up to note the role of the syphilitic neuroinvasion for the development of primary movement disorders. Moreover, we believe that any patient presenting with a movement disorder should have a thorough neurological examination of pupillary reflex, and if any abnormality is present, syphilitic laboratorial tests should be done.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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