Keywords: Corticobasal degeneration, neurosyphilis, parkinsonism, parkinsonism-plus, progressive supra-nuclear palsy
Neurosyphilis can be associated with a variety of clinical manifestations. It is traditionally known throughout the history of medicine as the ''the greater mimicker.'' After the discovery of penicillin, the improvement of sanitation systems, and public health care, the incidence of syphilis reduced significantly. However, over the past decades, there was a paradoxical increase in the percentage of syphilis atypical manifestations because of unknown causes.
In this context, parkinsonism-plus syndrome (PPS) is a group of neurodegenerative diseases featuring the cardinal signs of Parkinson's disease with additional clinical manifestations that distinguish them from simple idiopathic Parkinson's disease. Some of the diseases included in this definition are multiple system atrophy, progressive supra-nuclear palsy (PSP), and corticobasal degeneration (CBD).
There are only a few cases of neurosyphilis associated with PPSs that have been reported in the literature. To the authors' knowledge, there are only two case reports. To be more specific, one individual developed CBD in the context of syphilis infection and the other presented PSP.,
Herein, we would like to report a case of an elderly woman who presented to our emergency department with abnormal gait and progressive visual disturbance, probably secondary to neurosyphilis.
A 64-year-old female was admitted to our hospital because of vision problems, gait disturbances, and cognitive impairment within 6 months of onset. The patient complained of stiffness, short-stepped gait, dragging of feet along the ground, and intermittent freezing while walking. Also, she reported the necessity to turn the head down to follow visual stimuli. Four months into her illness, she noticed difficulty in opening her mouth, chewing, and swallowing. She was previously healthy, and her family history was unremarkable for neurological diseases.
The neurological examination revealed axial and asymmetric (right >left) bradykinesia, rigidity, and a mild rest tremor [Supplementary Material – Video]. A hypomimia, hypophonia, and increased flexion of the trunk were observed. She had marked gait initiation difficulty, which was slow along with shortened steps and ''en-bloc'' turning. The pupils were bilaterally small and reacted in size to a near object but did not constrict when exposed to bright light. The conjugate eye movements showed a defective downward gaze. The muscle strength, deep tendon reflex, sensory exam, and other cranial nerves were normal. On neuropsychological examination, the mini-mental state exam showed a moderate cognitive impairment (score 20 points). Also, reduced phonemic fluency was observed.
Routine laboratorial tests were within normal limits, except for a positive venereal disease research laboratory (VDRL) test (1:256) and fluorescent treponemal antibody test absorption (FTA-ABS) test. A cerebrospinal fluid (CSF) analysis showed positive VDRL (1:32) and CSF FTA-ABS test, 50 mg/dL of glucose (93 mg/dL plasma glucose), 14.0/mm3 (95% lymphocytes) of white blood cell count, 0 red blood cell count, and 101.2 mg/dL of protein. Human immunodeficiency virus serology was negative. A cranial computed tomography scan and brain and cervical spine magnetic resonance imaging (MRI) (1.5 T) were normal. An electro-encephalogram showed diffused slow waves.
The patient was treated with a course of aqueous crystalline penicillin G 24 million units IV daily, administered as 4 million units every 4 hours for 14 days. By the end of the course of treatment, her mental state and speech had improved significantly. She was followed up in the out-patient clinic at regular intervals. Six months after, the patient had a full recovery of her conjugate eye movements and cognitive functions. New CSF analysis was normal, including the VDRL-CSF that was negative. Also, the electro-encephalogram after penicillin treatment did not show abnormal electrical activity.
Upon further questioning, the patient reported that about 2 months after starting the gait disturbance, she was evaluated by a general practitioner who prescribed 100 mg of levodopa and 25 mg of benserazide three times a day. No improvement of her abnormal movements was observed after 2 weeks, and she discontinued the medication without medical advice.
Parkinsonism-plus, also known as atypical parkinsonism syndrome, was already described with many types of infections, drugs, and metabolic and cerebrovascular diseases. In this context, the diagnosis of PSP, CBD, multiple system atrophy, and Lewy body dementia is sometimes challenging. Distinguishing features can be subtle and should be systematically searched in order to successfully diagnose and treat patients. It is worthy of mentioning that less than 1% of the cases presenting with atypical parkinsonism are secondary to syphilis. Thus, the clinician should be highly suspicious of PPS to ascertain the diagnosis.
There are only a few case reports of parkinsonism-plus following neurosyphilis. We identified two cases after a thorough review of the English literature, and we compared them with the present case [Table 1]., A literature search was performed in Embase, Google Scholar, Medline, Scielo, and ScienceDirect using a set of terms that included parkinsonism, tremor, and syphilis [Supplementary Material – Other 1].
In the literature, two individuals developed PSP and one presented CBD, probably associated with neurosyphilis. The hypothesis that they developed these clinical manifestations because of syphilis can be supported by three facts. First, all the individuals showed at least a slight improvement in the movement disorder after the treatment with penicillin. Second, no response with levodopa therapy was achieved when attempted. Third, three patients had abnormalities in the electro-encephalogram, which are commonly found in syphilitic individuals.
When we analyze the PPS cases considering the data on movement disorders caused by neurosyphilis, important distinctions are found. The majority of the population affected by PPS was female and 10 years older when compared to the other abnormal movements. Interestingly, only gait disturbances do not fully subside after penicillin treatment in individuals with PPS, which may be explained by permanent damage caused by Treponema pallidum infection. In this way, the antibiotic can lead to a limited improvement of the related neuronal inflammation. Moreover, abnormalities in gait by neurosyphilis could be associated with the spinal cord and peripheral nervous tissue lesions.
Page et al. reported an interesting case of an individual who only developed vertical supra-nuclear gaze palsy in association with syphilis. Their case did not describe the occurrence of an abnormal movement, but it was probably the first to mention a pathophysiological mechanism of neurosyphilis involved in eye abnormal movements. They hypothesized that the gaze palsy occurred because of the invasion of the mesodiencephalic junction by Treponema pallidum. In the report by Murialdo et al., the brain MRI showed micro-vascular lesions characterized as vasculitis in the mid-brain, possibly related to syphilis. Therefore, the neuroimaging findings by Murialdo et al. may support the hypothesis previously assumed by Page et al.
Ballan and Tison described a case presented by Jean Lhermitte and colleagues in 1925 at the session of the French Neurological Society. The individual had a clinical presentation that today would resemble CBD. Ballan and Tison excluded neurosyphilis as a possible cause because of the fact that the patient did not show Argyll Robertson pupils. We believe that the patient reported by Jean Lhermitte et al. probably had syphilis. One fact that can support this hypothesis is that the individual had a positive Bordet–Wasserman reaction, which was a common test at the time the study was published for the diagnosis of syphilis. Also, the patient had urinary symptoms that were not clearly described and could be related to this sexually transmitted disease.
Another important finding is the presence of pupillary abnormalities. They occur in almost half of the patients with syphilis and probably constitute the most relevant early ocular sign of this disease. Furthermore, in a literature review, Argyll Robertson pupils were found in 54.90% of the individuals who developed a movement disorder following neurosyphilis. Argyll Robertson first assumed that the Argyll Robertson pupils were caused by a pathologic condition of the ciliospinal nerves. However, after a large amount of published anatomical and pathological evidence, the area of the nucleus Edinger–Westphal was described as the most plausible site of the lesion.
PPSs associated with neurosyphilis have been rarely reported in the literature. This is the second case to document the occurrence of a PSP because of syphilis. In this way, patients presenting with atypical parkinsonism should be thoroughly examined, especially if any pupillary abnormality is observed.
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