Parkinsonism Following SARS‐CoV‐2 Infection Unmasks a Genetic Twist

A broad spectrum of neurological sequelae has been associated with SARS-CoV-2 infection. Movement disorders remain uncommon, with higher prevalence of myoclonus, ataxia

bilaterally, worse on the left (Fig. 1G). Blood/CSF investigations (Table S1), NCS/EMG and autonomic testing were unremarkable. Neurocognitive assessment showed global cognitive impairment, mostly in anterior and subcortical regions.
Levodopa (100 mg TDS) improved his mobility significantly, while cognition and communication remained considerably affected and severe hypophonia persisted despite vocal cord palsy resolution. After one year, he experienced an acute episode of confusion and anarthria followed by general regression. Brain MRI with DWI (5 days post episode) remained unchanged. After increasing levodopa to 500 mg/day, he gradually recovered to his preceding deficient baseline.
Past medical history included hypercholesterolaemia and previous Miller-Fisher syndrome. He had no prodromal parkinsonian features, migraines, seizures, significant cognitive dysfunction, or neurotropic medication use. His father died after recurrent strokes in his 50s.
Neurological examination (Video 1) revealed hypomimia, pseudobulbar affect (inappropriate laughing) and barely audible whispered one-word responses. He had gaze impersistence. No tremor, dystonia, or dysmetria was found. He had asymmetric (worse on right) bradykinesia and rigidity. His power was normal with globally brisk reflexes, flexor plantar responses, and absent clonus. There were no sensory abnormalities. His postural reflexes were impaired. He had a shuffling gait with slightly stooped posture and bilaterally reduced arm swing.
His clinical presentation was initially attributed to hypoxic ischemic damage and/or SARS-CoV-2-related leukoencephalopathy. Diffuse small vessel disease with either monogenic or sporadic etiology was proposed given his stable serial neuroimaging findings. The former was considered more likely given his suggestive family history and minimal vascular risk factors. Genetic testing detected a heterozygous pathogenic variant NM_000435.3:c.1364G > T p.(Cys455Phe) in NOTCH3, which is associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Discussion
This case uniquely illustrates post-SARS-CoV-2 parkinsonism heralding previously undiagnosed CADASIL. Severe SARS-CoV-2-related pneumonitis and encephalopathy preceded a prolonged clinical course with severe cognitive and motor deficits and evolution to asymmetric parkinsonism with evidence of presynaptic nigrostriatal dysfunction. Key features prompting further investigation for monogenic vasculopathy included neuroimaging suggestive of extensive small vessel disease, history of early recurrent strokes in a first-degree relative, and absence of significant vascular risk factors.
CADASIL is a rare autosomal dominant disorder due to lossof-function NOTCH3 variants leading to accumulation of abnormal transmembrane deposits on vascular smooth muscle cells and impaired vascular function. Its usual stepwise progression includes migraine with aura, transient ischemic attacks, ischemic strokes, and dementia. 3,4 Parkinsonism is a late albeit not rare manifestation 5 characterized by progressive supranuclear palsy-like syndrome, lower body and asymmetric motor involvement, cognitive impairment and limited levodopa response. 6 DaTscan can demonstrate reduction of tracer uptake in the putamen with inconstant caudate involvement. 5 Although most cases of parkinsonism in CADASIL were not levodopa responsive, there is little evidence of limited levodopa response in very few reports. In this patient, diffuse small vessel disease involving the nigrostriatal or thalamocortical pathways (Fig. 1) might have caused presynaptic dopaminergic, as documented by his abnormal DaTscan, and explain a favorable response to levodopa.
A literature review identified a total of 20 cases of post-SARS-CoV-2 parkinsonism, but CADASIL was never diagnosed. 7 We identified six cases of CADASIL decompensation due to SARS-CoV-2 infection, and parkinsonism was not reported in any of these ( Table 1). It is unclear whether these is the same series reported by Noui et al. 8 This is the first description of post-SARS-CoV-2 levodoparesponsive parkinsonism in the context of CADASIL. We believe that parkinsonism is attributable to CADASIL, that was unmasked by SARS-CoV-2 infection. Extensive CADASIL small vessel arteriopathy can affect the structural and functional integrity of the basal ganglia thereby causing vascular parkinsonism. SARS-CoV-2 infection could trigger this process by creating an inflammatory environment predisposing vascular endothelial injury. 9 This case highlights the importance of investigation for other etiologies in cases of post-SARS-CoV-2 parkinsonism and supports the hypothesis that SARS-CoV-2 infection can unmask parkinsonism from other aetiologies, rather than directly causing it.