New-Onset Progressive Ataxia in a 66-Year-Old Woman with Longstanding Parkinson’s Disease: A Case Report Open Access

Idiopathic Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of bradykinesia, along with rest tremor or rigidity, and a slowly progressive course of disease. According to the current MDS-PD criteria, the presence of certain exclusion criteria rules out PD, while red flags and supportive criteria need to be carefully considered in establishing a diagnosis of PD [1]. The presence or emergence of such exclusion criteria or red flags suggests other pathologies causing neurodegenerative or symptomatic parkinsonism, such as multiple system atrophy (MSA), progressive supranuclear palsy, or normal pressure hydrocephalus. With this case report, we want to emphasize the importance of routine follow-up examinations of patients with PD, prompting a new diagnostic work-up if exclusion criteria or red flags emerge even in later stages of the disease. Additionally, we want to highlight clinical symptoms and management of infratentorial superficial siderosis (SS), an under-recognized disease entity that typically presents with hearing loss, movement abnormalities such as ataxia and pyramidal signs, but that might cause parkinsonism in rare instances.

We report the case of a 66-year-old woman who first presented to our clinic in June 2022. The patient’s disease course and its milestones are shown schematically in Figure 1.

The patient first noticed clumsiness and stiffness in her right upper extremity in 2008, preceded by a several-year history of progressive hyposmia and a sleep disorder consistent with REM sleep behavior disorder (RBD). In 2011, she was first examined by a neurologist who noted right dominant rigidity and bradykinesia of the upper and lower limbs and she was diagnosed with PD. Magnetic resonance imaging (MRI) of the brain at that time showed hemosiderin deposition in the infratentorial regions, bilateral parieto-occipital sulci, and posterior interhemispheric fissure, which were then traced back to a suspected (yet clinically asymptomatic) previous traumatic subarachnoid bleed. Medical history at that time was positive for osteoporosis (treated with alendronic acid), degenerative spinal changes, and cigarette smoking.

Parkinsonian symptoms slowly progressed over the next 7 years, but a marked response to dopaminergic therapy was maintained. Initially, she received pramipexole and rasagiline, which were combined with levodopa/benserazide in 2016.

In 2018, she experienced a rapidly progressive worsening of gait, subsequently leading to substantial disability and a suspected diagnosis of MSA. That year, bilateral marked dopaminergic degeneration was verified by a dopamine transporter (DaT) scan. Cerebral MRI showed extensive, predominantly infratentorial, hemosiderin depositions. There were no clinical signs or symptoms of orthostatic hypotension, and bladder scan was negative for residual urine. Gait continued to deteriorate over the next 4 years, leading to the patient’s first presentation to our clinic in June 2022.

Medical history at that time included collagenous colitis, osteoporosis (complicated by several, predominantly vertebral fractures), and left knee joint replacement due to arthrosis under spinal anesthesia in 2016. History was otherwise negative for spinal surgery or trauma. Family history was negative for PD or other movement disorders; her mother had died of stroke at the age of 60 years. Genetic testing for PD had never been performed.

Medication at presentation in 2022 included levodopa/carbidopa/entacapone, ropinirole, rasagiline, and anti-osteoporotic agents (denosumab twice a year, calcium, and vitamin D supplement). The patient reported a new onset of mild dyskinesias.

Examination of cranial nerves revealed mild gaze-evoked nystagmus and marked hypomimia. Subjectively, the patient reported mild yet progressive hearing loss and longstanding hyposmia. Her speech was impaired owing to scanning dysarthria. Motor examination revealed mild rigidity of the neck and extremities, marked bradykinesia (right dominant), and intermittent resting tremor of the upper and lower extremities. Postural tremor was present in the upper extremities. Finger-nose and heel-shin tests showed dysmetria and intention tremor. At the time of the examination, the patient was slightly dyskinetic. Pyramidal signs were absent. Gait was severely impaired, characterized by small steps, reduced foot lifting and arm swing, and turning required multiple steps. Posture was inclined forward and to the right. Tandem gait was severely unsteady. Gait was additionally impaired by pain due to progressive knee arthrosis. A video of the neurological exam showing scanning dysarthria, bradykinesia, atactic finger-nose test, and abnormal gait including severely impaired tandem gait is available online as supplementary Video S1 (for all online suppl. material, see https://doi.org/10.1159/000545411). Note the presence of dyskinesias, particularly during speech testing.

Routine laboratory testing was unremarkable. There were no clinical signs or symptoms of autonomic dysfunction such as orthostatic hypotension or urinary retention. Although a polysomnographic evaluation had never been conducted, the patient reported longstanding sleep problems consistent with RBD.

Cerebral MRI (Fig. 2) showed extensive, predominantly infratentorial superficial (hemo-)siderosis. There was significant atrophy of the anterior cerebellar hemispheres and vermis (Fig. 3). Contrast-enhanced MRI of the spine showed a ventral intraspinal fluid collection extending from C6 to Th6 (Fig. 3). No dura leak or tear was detected in high-resolution constructive interference in steady-state reverse sequences. Multiple disk protrusions were present in the cervical spine denting the dural sac (Fig. 3); however, there was no disk herniation. Dural superficial hemosiderin depositions were observed in the cervical spine and, to a lesser degree, in the thoracic and lumbar spine. There was no arteriovenous malformation in CT angiography. In-111 DTPA cerebrospinal fluid (CSF) scintigraphy did not show any tracer leakage. CSF analysis was remarkable for increased red blood cells (400 erythrocytes per microliter) as a sign of ongoing bleeding [2]; there was no CSF pleocytosis. Beta-amyloid 1-42/1-40 ratio was within normal limits. Audiometry revealed mild symmetric hearing loss in the high-frequency range, while otorhinolaryngological examination was otherwise normal. Neuropsychological testing was performed by a trained neuropsychologist and pointed to possible non-amnestic mild cognitive impairment.

In the absence of an evident dural leak, an epidural blood patch was performed at vertebral level of L2/L3 in October of 2023. Clinical follow-up 14 months later revealed progression of levodopa-induced dyskinesias and the occurrence of wearing-off effects, while cerebellar signs (scanning dysarthria and limb and gait ataxia) remained stable. There was no progression of superficial hemosiderin depositions in cerebral MRI.

This case gives rise to the discussion of the following points: the value of clinical MDS-PD diagnostic criteria to differentiate PD from symptomatic parkinsonism, the rare but potentially treatable condition of SS, and the question of whether and how SS can cause symptomatic parkinsonism. In 2011, the patient presented with asymmetric bradykinesia and rigidity. At that time, MRI already showed hemosiderin deposits, retrospectively suspicious of mild SS, which were not considered to be related to the patients’ clinical symptoms. In the presence of typical parkinsonian symptoms and two supportive criteria (clear beneficial response to levodopa and hyposmia existing for some years) and the absence of relevant exclusion criteria or red flags, a diagnosis of PD was made. The disease course was in line with that seen in PD, until 2018 when a rapid clinical deterioration with subsequent emergence of cerebellar symptoms occurred.

Possible explanations for this disease course include a diagnosis of PD with subsequent development of additional symptoms due to SS or, alternatively, the presence of symptomatic parkinsonism with cerebellar signs due to SS. Symptom onset in the patient was unilateral, and the cardinal motor features of parkinsonism remained right dominant in our patient. While an abnormal DaT scan cannot differentiate PD from atypical parkinsonian symptoms, it confirms the presence of degeneration of the nigrostriatal system in our patient, making other non-degenerative causes of parkinsonism less likely.

After a disease duration of more than 10 years, the emergence of a red flag (relatively rapidly progressive gait impairment) and an exclusion criterion for PD (cerebellar abnormalities) rightly raised doubts regarding the diagnosis of PD and the concurrence of parkinsonism and cerebellar symptoms led to a presumed diagnosis of MSA by the treating physician. However, the longstanding history of PD and rather acute change in clinical presentation prompted us to perform a new diagnostic work-up of this case, which led us to a diagnosis of SS.

Classical symptoms of SS include progressive cerebellar ataxia, sensorineural hearing loss, and pyramidal signs. Cognitive impairment, in particular executive dysfunction, is another clinical feature of SS. In cases of dural tears leading to CSF leaks, patients may also report signs of craniospinal hypovolemia [2].

Dura tears evoked by osteophytes, calcified disk herniations, (surgical) trauma, or spinal tumors are a common etiology of SS. Ventral intraspinal fluid collection, as present in our patient, suggests a dural tear as a likely source of SS [2]. However, we could not identify a dural tear nor an apparent cause for one neither using structural nor scintigraphic imaging modalities.

SS is caused by the deposition of neurotoxic hemoglobin breakdown products along superficial, CSF-rinsed regions of the central nervous system. Consequently, the basal ganglia are usually spared by this process and extrapyramidal movement disorders are a rare presentation of SS [3]. While the substantia nigra is not in direct contact to neurotoxic hemoglobin breakdown products carried by CSF, DaT scan was abnormal in this patient, which supports the notion of parkinsonism being caused by PD-type neurodegeneration rather than SS-associated neurodegeneration in this case. Nonetheless, in other cases, SS may be misdiagnosed (e.g., as MSA or PD [4]) due to clinical similarities or even overlooked.

Hemosiderin-induced damage of cochlear or retrocochlear structures, such as the vestibulocochlear nerve, might be responsible for the frequent finding of hearing loss in SS [5]. Therapeutic management of SS is best targeted at the underlying culprit. This includes surgical closure of dural defects or addressing vascular malformations and tumors. Epidural blood patches remain an option in cases without proof of a CSF leak but generally do not appear to be a promising therapeutic strategy in the presence of intraspinal fluid collection [2]. While symptoms of craniospinal hypovolemia and progression of signs of SS might be stopped or delayed, clinical improvement following surgical therapy seems to get less likely with disease duration [2]. If no apparent bleeding source can be identified, pharmacological treatment with peroral iron chelators remains an option. Deferiprone, an agent that can cross the blood-brain barrier, has recently been found to stabilize or improve neurological symptoms in six out of eleven studies, while rates of adverse events like anemia or agranulocytosis were relatively high [6].

In the present case, we could not identify a dural leak, even though the existence of a ventral intraspinal fluid collection suggests the presence of one. Hence, surgical intervention was not an option in this case and, considering the potential side effects and preexisting polypharmacy in this patient, iron chelation did not seem like a favorable option. Even though the existing literature suggests a low probability of success [2], we still chose to perform an epidural blood patch in this patient for several reasons. On the one hand, the patient was progressively and severely impaired by ataxia, and the procedure has a low risk of complications and side effects. On the other hand, the presence of a ventral intraspinal fluid collection suggested an underlying dural leak, even though we could not detect one on standard imaging. Cerebellar signs (scanning dysarthria, limb/gait ataxia) were stable at 1-year clinical follow-up, and cerebral superficial hemosiderin deposition did not progress in cerebral MRI, while characteristic signs and symptoms of later stage PD (levodopa-induced dyskinesias, end-of-dose wearing-off) increased. While we cannot fully confirm that epidural blood patch and consequent stability of imaging and clinical parameters in this case are causally related, the chronology and disease course of the patient at least suggests that this procedure might present a low-threshold therapeutic option at least in cases where other treatments are not promising.

Few reports exist in which SS has been misdiagnosed as PD or has been suggested as the cause of parkinsonism. However, these cases were markedly different from our patient. In the case presented by Bordes et al. [4], the initial diagnosis of PD was not consistent with the MDS-PD criteria. Two other cases reported with SS presented with symmetric parkinsonism early in the disease course and lacked a significant response to levodopa [7, 8], with the former being a red flag and the latter a supportive feature according to the MDS-PD criteria [1]. Tremor was not reported in either of these patients.

Taking into account the reported sparing of the basal ganglia in the widespread disease process of SS, De Mase et al. [3] suggested a role of other brain structures (e.g., midbrain and cerebellum) and disruption of their connections to the basal ganglia as a possible pathophysiology of movement disorders like parkinsonism in SS. In our case, MRI signs of SS were already present at the time of the first diagnosis of PD in 2011, 3 years after the patient first noticed parkinsonian motor symptoms. Hence, we cannot exclude a potential role of hemosiderin depositions in the etiology of parkinsonism in this patient. Nevertheless, we favor a diagnosis of both incidental PD and SS independently from each other, rather than symptomatic parkinsonism, for several reasons. On the one hand, as discussed above, the PD diagnosis conformed to the MDS-PD criteria; all supportive criteria (marked response to dopaminergic agents, rest tremor, dyskinesia, hyposmia) were present, while there were neither red flags nor exclusion criteria for 10 years. Hyposmia, a hallmark non-motor symptom of PD [9], had manifested several years before the onset of motor symptoms. However, one should not dismiss that hyposmia has recently been described as a common finding in SS, too [10]. The patient also reported sleep problems consistent with RBD, although a polysomnographic work-up had never been performed. Additionally, the patient had an abnormal DaT scan, hence not complying with the suspected pathophysiological mechanism of SS leading to parkinsonism [3]. Additionally, motor symptoms of PD emerged approximately 10 years prior to gait ataxia as a classic symptom of SS in our patient; this time gap, in light of the rarity of movement disorders in SS, makes a causal relationship in our opinion even less likely. Finally, the progression of features typical of later stage PD (levodopa-induced dyskinesias, end-of-dose wearing-off) and, simultaneously, stability of cerebellar ataxia after epidural blood patch support the hypothesis of both PD and SS co-occurring incidentally in this patient. This case report is the first to report the co-occurrence of PD and SS in one individual. The historical, clinical, and imaging features of this case suggesting incidental PD and SS or symptomatic parkinsonism due to SS, respectively, are summarized in Table 1.

In conclusion, we present a case of idiopathic PD and the rare entity of SS occurring in one individual in parallel. The MDS-PD criteria are a useful tool to differentiate PD from atypical parkinsonian disorders and symptomatic parkinsonism. The value of this case report is that it demonstrates that the clinical diagnosis of PD needs to be reevaluated regularly and that an atypical disease course in a patient with PD warrants a new diagnostic work-up. Additionally, SS must be taken into consideration as a possible and treatable cause of symptomatic parkinsonism in patients presenting with bilateral, symmetric, and poorly levodopa-responsive parkinsonism. Moreover, epidural blood patch can be considered as a low-risk therapeutic intervention in SS cases where no dural leak can be identified and medical treatment seems unfavorable. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material.

We would like to thank the patient for giving us the opportunity to report on this interesting case.

No formal ethic approval was required for this type of study (case report) in accordance with local and national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images and videos.

The authors declare no conflicts of interest in relation to this manuscript. Financial disclosures of the last 3 years are as follows: L.G.K. – travel funding and honoraria from AbbVie, Johnson & Johnson, Merz, and Stada; P.K.W. – travel funding from Ipsen and honoraria from Bial; M.K. – honoraria from UCB Pharma, travel funding and honoraria from AbbVie, Allergan, Merz, and Stada, and advisory boards for AbbVie and Merz; P.S. – travel funding, honoraria for talks, and advisory boards from AbbVie, Bial, Boston Scientific, and Merz.

This study was not supported by any sponsor or funder.

Conceptualization, validation, and project administration, L.G.K. and P.S.; methodology and data curation, L.G.K., P.K.W., M.K., and P.S.; software, formal analysis, writing – original draft preparation, and visualization, L.G.K.; investigation, L.G.K., P.K.W., and P.S.; resources, L.G.K. and P.K.W.; writing – review and editing, P.K.W., M.K., and P.S.; supervision, P.S. All authors have read and agreed to the published version of the manuscript.

The data that support the findings of this study are not publicly available due to ethical reasons (containing information that could compromise the privacy of reported patient) but are available from the corresponding author (P.S.) upon reasonable request.