Encephalopathic Syndrome Research Articles

Endovascular Treatment for Cerebral Venous Sinus Thrombosis: Comparison among Different Endovascular Procedures.

Cerebral venous sinus thrombosis (CVST) is a rare, treatable cause of stroke. Even though CVST has an established medical treatment, 15% of patients remain refractory to treatment. These patients may be candidates for endovascular treatment (EVT), yet the selection of patients remains a challenge. The study aims to understand the profile and outcome of patients treated with EVT and the type of procedure associated with good outcomes. This is a single-center, retrospective analysis of CVST patients who underwent EVT from 2009 till 2022. Patients who received only medical management were excluded. Modified Rankin Scale (mRS) ≤2 at 3 months was taken as the primary outcome. Secondary outcomes assessed were hospital stay, death, recurrence, mRS ≤ 2 at discharge, and angiographic recanalization. Fifty-two patients were included. Twenty-eight (53.8%) were males; the mean age was 33.3 ± 12.3 years. Headache (n = 44, 84.6%) predominated among the symptoms. The common risk factors were anemia (n = 13, 25.5%) and hyperhomocysteinemia (n = 13, 25.5%). Worsening of sensorium (n = 21, 40.3%) and non-improvement of symptoms (n = 15, 28.8%) were the common indications for the procedure. Twenty-five (48.1%) people underwent in situ thrombolysis (IST). Death occurred in eight (15.3%) patients. Thirty-six (73.5%; 36/49) patients had a good outcome at 3 months. IST had a significantly better outcome (mRS ≤ 2, n = 20, 80%) compared to other procedures (P = 0.04). Hospital stay was lesser in the IST subgroup, but without statistical significance. Midline shift >5 mm (odds ratio [OR] 6.8 [1.5-30.9], P = 0.01) and Glasgow Coma Scale <9 before the procedure (OR 27.2 [3.1-236.4], P = 0.002) predicted bad outcomes at 3 months. Female gender (OR 4.5 [1.07-8.8], P = 0.03), presence of altered sensorium (OR 10.2 [1.2-87.5], P = 0.01), encephalopathic syndrome (P = 0.02), presence of parenchymal bleed (OR 3.7 [0.9-4.5], P = 0.04), and midline shift (OR 4.8 [1.1-20.2], P = 0.03) were associated with poor outcome at discharge. EVT yielded good outcomes in carefully selected, medically refractory patients of CVST. IST performed well compared to other procedures.

Outcomes following surgical interventions for hypothalamic hamartomas: protocol for a systematic review and individual patient data meta-analysis

IntroductionHypothalamic hamartomas (HHs) are deep-seated congenital lesions that typically lead to pharmacoresistant epilepsy and a catastrophic encephalopathic syndrome characterised by severe neuropsychological impairment and decline in quality of life. A...

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady‐state conditions to fine‐tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4‐associated mtDNA depletion syndrome.

Recurrent encephalopathy associated with pegylated beta-interferon treatment

A 62-year-old woman with a history of multiple sclerosis (MS) presented with recurrent episodes of confusion, dysarthria and gait difficulties. These episodes occurred about 3 days after administration of pegylated interferon-beta-1a (Plegridy®) and resolved spontaneously in around 4 days. The brain MRI scan, laboratory findings and cerebrospinal fluid analysis during these episodes were negative for other causes of encephalopathy. She discontinued treatment with interferon and was started on teriflunomide, experiencing no recurrence of symptoms. We believe that interferon was responsible for this patient's recurrent encephalopathic syndrome, possibly due to its effects on inflammatory cytokines and endothelial dysfunction.

The psychosocial impact of caring for children with Dravet Syndrome

This study examined the psychosocial impact on parents of children affected by Dravet Syndrome (DS), a rare drug-resistant developmental encephalopathic epileptic syndrome which affects children at an early age and that involves severe cognitive, behavioral, and motor impairments. DS has a major negative impact on caregivers, mainly on their physical and mental health, and on their social relationships and economic resources. Similarly, it has been suggested that the quality of life of caregivers and children with DS is lower compared to the general population, especially because of the severe and frequent seizures suffered by the child, leaving caregivers with heavy burdens. The main aim of the current study was to assess in detail the psychosocial impact that having a child with DS represents for their parents or caregivers. To this end, a standardized assessment tool was used, and the results were compared to those of a control group. The results highlighted critical differences in most of the areas explored, revealing a marked difference between parents caring of children with DS and parents of normotypically developing children in the psychosocial wellness. This study provides important qualitative data to help us understand and identify the complexity of DS.

Posterior reversible encephalopathic syndrome in systemic lupus erythematous: A case report

Posterior reversible encephalopathy syndrome (PRES) implies to a reversible subcortical vasogenic brain edema, which leads to some acute neurological symptoms. PRES occurs usually in the setting of renal failure, blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia.This is a 40 year old female patient with history of systemic lupus erythematous (SLE) from twenty years ago, admitted to our neurology ward due to severe and refractory headache with multiple convulsive events.Brain MRI showed vasogenic brain edema in occipito-parieto-frontal lobes white matter compatible with PRES. Treatment is omitting of the etiology, but in these patients, discontinuation of immunosuppressive drugs is not possible and probably intravenous methylprednisolone pulse is a good treatment option especially in patient without response to aggressive control of blood pressure.

COVID-19-related neuropathology and microglial activation in elderly with and without dementia.

The actual role of SARS‐CoV‐2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS‐CoV‐2 or by pre‐existing conditions. Findings of 9 Coronavirus disease 2019 (COVID‐19) cases and 6 matched non‐COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS‐CoV‐2, lymphocytes, astrocytes, endothelium, and microglia. A semi‐quantitative scoring was applied to grade microglial activation. Thal‐Braak stages and the presence of small vessel disease were determined in all cases. COVID‐19 cases had a relatively short clinical course (0–32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID‐19 cases showed non‐SARS‐CoV‐2‐specific changes including hypoxic‐agonal alterations, and a variable degree of neurodegeneration and/or pre‐existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS‐CoV‐2 were detected. Microglial activation in the brainstem was significantly greater in COVID‐19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS‐CoV‐2 infection. In COVID‐19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID‐19, cortical neuroinflammation is not related to COVID‐19 per se but mostly to pre‐existing neurodegeneration. COVID‐19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS‐CoV‐2‐specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID‐19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the “COVID‐19 encephalopathic syndrome” in the elderly.

Limbic encephalitis due to antineuronal antibodies

Abstract. Limbic encephalitis (LE) is an encephalopathic syndrome caused by antineuronal antibodies against extracellular or intracellular neuronal structures. LE may present clinically with a variety of symptoms, including epileptic seizures, cognitive and memory deficits, and personality changes. Whereas LE mediated by antibodies against intracellular antigens is frequently of paraneoplastic origin and associated with a poorer prognosis, LE mediated by antibodies against extracellular or transmembrane antigens causes potentially reversible neuronal dysfunction and, given early diagnosis and treatment, is associated with a comparatively benign prognosis. We present and discuss four different cases of autoantibody-mediated LE, with different clinical outcomes and both with and without paraneoplastic origin. Red flags pointing to the diagnosis of antibody-mediated LE include rapidly progressing personality changes or memory deficits and disorientation, novel epileptic seizures, and a history of neoplasia.

FBXL4 deficiency increases mitochondrial removal by autophagy

Pathogenic variants in FBXL4 cause a severe encephalopathic syndrome associated with mtDNA depletion and deficient oxidative phosphorylation. To gain further insight into the enigmatic pathophysiology caused by FBXL4 deficiency, we generated homozygous Fbxl4 knockout mice and found that they display a predominant perinatal lethality. Surprisingly, the few surviving animals are apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss. One‐year‐old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mtDNA depletion, whereas lysosomal proteins are upregulated. Fibroblasts from patients with FBXL4 deficiency and human FBXL4 knockout cells also have reduced steady‐state levels of mitochondrial proteins that can be attributed to increased mitochondrial turnover. Inhibition of lysosomal function in these cells reverses the mitochondrial phenotype, whereas proteasomal inhibition has no effect. Taken together, the results we present here show that FBXL4 prevents mitochondrial removal via autophagy and that loss of FBXL4 leads to decreased mitochondrial content and mitochondrial disease.

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.

Clinical Study on the Melarsoprol-Related Encephalopathic Syndrome: Risk Factors and HLA Association.

Melarsoprol administration for the treatment of late-stage human African trypanosomiasis (HAT) is associated with the development of an unpredictable and badly characterized encephalopathic syndrome (ES), probably of immune origin, that kills approximately 50% of those affected. We investigated the characteristics and clinical risk factors for ES, as well as the association between the Human Leukocyte Antigen (HLA) complex and the risk for ES in a case-control study. Late-stage Gambiense HAT patients treated with melarsoprol and developing ES (69 cases) were compared to patients not suffering from the syndrome (207 controls). Patients were enrolled in six HAT treatment centres in Angola and in the Democratic Republic of Congo. Standardized clinical data was obtained from all participants before melarsoprol was initiated. Class I (HLA-A, HLA-B, HLA-Cw) and II (HLA-DR) alleles were determined by PCR-SSOP methods in 62 ES cases and 189 controls. The principal ES pattern consisted in convulsions followed by a coma, whereas ES with exclusively mental changes was not observed. Oedema, bone pain, apathy, and a depressed humour were associated with a higher risk of ES, while abdominal pain, coma, respiratory distress, and a Babinski sign were associated with higher ES-associated mortality. Haplotype C*14/B*15 was associated with an elevated risk for ES (OR: 6.64; p-value: 0.008). Haplotypes A*23/C*14, A*23/B*15 and DR*07/B*58 also showed a weaker association with ES. This result supports the hypothesis that a genetically determined peculiar type of immune response confers susceptibility for ES.

A patient-specific induced pluripotent stem cell model for West syndrome caused by ST3GAL3 deficiency.

ST3GAL3 encodes the Golgi enzyme beta-galactoside-alpha-2,3-sialyltransferase-III that in humans forms, among others, the sialyl Lewis a (sLea) epitope on proteins. Functionally deleterious variants in this gene were previously identified in patients with either non-syndromic or syndromic intellectual disability such as West syndrome, an age-dependent epileptic encephalopathic syndrome associated with developmental arrest or regression. The aim of this study was to further elucidate the molecular and cellular mechanisms causing West syndrome by lack of ST3GAL3 function. For this purpose we generated induced pluripotent stem cell (iPSC) lines from fibroblasts obtained from a patient with West syndrome, carrying a variant in exon 12 (c.958G>C, p.(Ala320Pro)) of ST3GAL3, and a healthy sibling, using lentiviral reprogramming. iPSCs and cortical neurons derived thereof were analysed by lectin blots, mRNA sequencing, adherence assays, and FACS. While no significant difference was observed at stem cell or fibroblast level between patient and control cells, patient-derived cortical neurons displayed an altered lectin blot staining pattern, enhanced adherence to a poly-L-ornithine/laminin-coated surface and decreased levels of neurons expressing T-box transcription factor brain 1. Our results suggest that changes in the sialylation pattern on the surface of specific neuronal cell types affect adhesive interactions during development, which in turn may cause subtle changes in tissue composition that could result in the occurrence of epilepsy and might impair neural development to an extent that is detrimental to the development and maintenance of normal cognitive functions.

Reversible Cerebrovascular Syndrome

Reversible cerebrovascular syndrome (RCVS) is clinico-radiological syndrome defined as severe recurrent thunderclap headache with or without seizures or neurologic deficits and constriction of cerebral arteries which resolves spontaneously within 1-3 months. RCVS affects patients in various racial and ethnic groups and in all age groups, although most commonly in the fourth decade of life. Headache is the main symptom. Headache is usually “thunderclap variety”, peaks within one minute and very intense. Many conditions and exposures have been linked to RCVS, including vasoactive drugs, metabolic disorder, vasculitis and the peripartum period. Associated strokes and cerebral hemorrhages are not uncommon. As complications we can see Localized cortical SAH (20-25%), Ischemic or hemorrhagic stroke (5-10%), posterior reversible encephalopathic syndrome ( PRES). Permanent sequelae of RCVS is usually benign entity. Prognosis is highly dependent on the occurrence of stroke (6-9%), otherwise, by definition, most resolve completely without any sequelae. Treatment is Symptomatic (pain, seizures, blood pressure control), trigger avoidance should be done (either activity or vasoactive substances), calcium channel blockers, IV magnesium and Short-course of steroids may be effective.

Neurologic and neuroimaging manifestations of Cantú syndrome: A case series.

To describe the neurologic and neuroimaging manifestations associated with Cantú syndrome. We evaluated 10 patients with genetically confirmed Cantú syndrome. All adult patients, and pediatric patients who were able to cooperate and complete the studies, underwent neuroimaging, including vascular imaging. A salient neurologic history and examination was obtained for all patients. We observed diffusely dilated and tortuous cerebral blood vessels in all patients who underwent vascular imaging. White matter changes were observed in all patients who completed an MRI brain study. Two patients had a persistent trigeminal artery. One patient had an occluded right middle cerebral artery. One patient had transient white matter changes suggestive of posterior reversible encephalopathic syndrome. Four patients had migraines with one patient having complicated migraines. Seizures were seen in early life but infrequent. The majority of patients had mild developmental delays and one patient had a diagnosis of autism. Cantú syndrome is associated with various neurologic manifestations, particularly cerebrovascular findings including dilated and tortuous cerebral vessels, white matter changes, and persistent fetal circulation. Involvement of the KATP SUR2/Kir6.1 subtype potentially plays an important role in the neurologic manifestations of Cantú syndrome.

Transient focal leukoencephalopathy with cerebral oedema as a presentation of cerebral amyloid angiopathy

Cerebral amyloid angiopathy affects the small-to-medium-sized cerebral arteries most commonly resulting in asymptomatic microhaemorrhages and symptomatic lobar brain haemorrhages. More unusually, it may present as an acute or subacute leukoencephalopathy....

Eosinophilic granulomatosis with polyangiitis (EGPA) and PRES: a case-based review of literature in ANCA-associated vasculitides

Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-sized vessel systemic necrotizing vasculitis and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The involvement of central nervous system in this condition is pretty rare. Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity described for the first time by Hinchey et al. (N Engl J Med 334(8):494-500, 1996) and characterized by MRI findings of reversible subcortical vasogenic edema predominantly in the white matter of posterior cerebral lobes. There are few case reports describing the concurrence of PRES with ANCA-associated vasculitides. We describe a case of PRES in a patient with a diagnosis of EGPA with a concise review of the literature. The exact cause of this syndrome is unknown. It has been related to eclampsia, drug-induced hypertension, renal insufficiency and also to rheumatologic diseases. Endothelial injury, hypertension and immunosuppressive medications can compromise the regulation of cerebral blood flow. In ANCA-associated vasculitides, patients presenting with symptoms of PRES represent a challenge to treatment with immunosuppressive medications. However, since an inflammatory process might be implicated, judicious use of these agents along with tight control of blood pressure and a supportive therapy may contribute to the resolution of the encephalopathic syndrome treating at the same time other manifestation related to the rheumatologic disease. Larger clinical studies are warranted to optimize the management of vasculitis-associated PRES.

A phase I study of oral darinaparsin in patients (pts) with advanced solid tumors (AST).

e13040 Background: Darinaparsin [Zinapar, ZIO-101(S-dimethylarsino-glutathione)], is a novel organic arsenic compound with in vitro and in vivo anticancer activity in tumor cell lines resistant to arsenic trioxide. An oral formulation is now available. Methods: This study used a 3+3 escalating design, dosing orally for 21 days followed by 7 days off (28 day cycle). Pts with AST refractory to standard therapy, ECOG performance score (PS) ≤ 2 and adequate organ function were treated. Study objectives were safety profile evaluation, pharmacokinetics (PK) and preliminary activity of oral darinaparsin. CTCAE v. 4.0 and RECIST 1.1 were used. Results: A total of 10 pts (8 males, 2 females), with ECOG PS 0=2, 1=8, mean age of 71 years (range: 60-81), median of prior therapies 3 (range: 1-4) were treated. A median of 2 cycles of darinaparsin was administered (range: 1-6). Dose limiting toxicities (DLT) were confusion (n=1; 400 mg), cognitive disturbance (n=1; 400 mg) and encephalopathic syndrome (n=1; 300 mg), reversible with drug discontinuation. The highest tolerable dose was 300 mg per day. Most frequent AEs were: hypokalemia, nausea (40% each), fatigue (30%), anemia, diarrhea, hypophosphatemia, pneumonia, vomiting (20% each). Most frequent grade ≥3 AEs were: hypokalemia, hypophosphatemia (20% each). Best overall response was stable disease (at 2 cycles), observed in 5 pts: adenocarcinoma of colon (2 pts), chordoma, adenocarcinoma of small bowel and carcinoma of tongue. PK analysis of 400 mg cohort (n=4) and 300 mg cohort (n=6) resulted in Tmax at 9 hr post treatment and Cmax slightly greater than dose proportional (p&lt;0.05). Steady-state trough levels were achieved on or before Day 5. Approximately 40 % greater Cmax was observed on D15 compared to D1 for the 300 mg cohort (p&lt;0.05) while unchanged at 400 mg. DLTs were observed when duration of exposure was more than 7 days and serum trough levels were 800 ng/ml or above. Conclusions: Oral darinaparsin is well tolerated at the dosage of 300 mg per day for 21days in a 28 day cycle in pts with AST. Preliminary evidence of clinical activity and a predictable PK profile justify further evaluation of darinaparsin in selected indications.

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Methylene Blue-Associated Serotonin Syndrome: A ‘Green’ Encephalopathy After Parathyroidectomy

Methylene blue (MB) infusion is frequently used to localize the parathyroid glands during parathyroidectomy and generally considered safe. Several recent reports suggest neurological toxicity and post-operative altered mental state typically after large dose infusions. The mechanism by which MB has neurotoxic effects in some patients remains uncertain. A 67-year-old male underwent lumbar laminectomy followed by parathyroidectomy. Postoperatively, he was comatose (Glasgow Coma Scale of 7) and underwent extensive neurological evaluation. Brain computed tomography (CT) imaging and CT angiography revealed no ischemia, vessel occlusion, or hemorrhage. Electroencephalogram (EEG) showed only slowing of cerebral hemispheric activity bilaterally. Over the next 48 h, his mental status slowly improved and the patient made a full neurological recovery (Glasgow Coma Scale 15). Methylene blue, when used in patients on antidepressant drugs, may be associated with a transient encephalopathic state and serotonin syndrome. Patients on antidepressants undergoing parathyroidectomy who may receive MB infusion should be considered for alternative parathyroid gland identification or discontinuation of the antidepressants before surgery. MB-associated serotonin syndrome is an increasing and under recognized ('green') post-operative encephalopathy that warrants education to critical care neurologists and other physicians.

VASCULAR PARKINSONISM IN AN ELDERLY WOMAN WITH MIXED CRYOGLOBULINEMIA ASSOCIATED WITH HEPATITIS C INFECTION

To the Editor: Central nervous system (CNS) involvement is rarely reported in patients infected with hepatitis C virus (HCV).1 Stroke, transient ischemia, lacunar infarction, or encephalopathic syndrome may occur. Mechanisms related to vasculitis induced by the mixed cryoglobulinemia frequently associated with HCV infection seem to generate neurological lesions.1, 2 Vascular parkinsonism (VP) is now recognized as a distinct clinicopathological entity,3, 4 especially in older people,5 although the validity of VP as a concept has been called into question since the original work of Critchley.6 VP accounts for 3% to 6% of all cases of parkinsonism in studies in which imaging or pathological analysis is used to support diagnosis.7 We report here a case of VP associated with mixed HCV-related cryoglobulinemia. An 83-year-old woman was hospitalized for rehabilitation after a gradual loss of autonomy related to gait problems, postural instability, and mild depression, all of which worsened after an episode of severe bronchopneumonia. Parkinson's disease had been diagnosed 6 years previously, but no improvement was observed on levodopa treatment. Four years after the onset of symptoms, the patient was admitted to a neurological facility. Magnetic resonance imaging showed microhypersignal for the basal ganglia (striatum, insula, thalamus), external capsule, periventricular white matter, and, to a lesser extent, geniculate bodies, cerebellar peduncles, and dentate nuclei. VP was diagnosed. The dose of levodopa was increased, but no real improvement followed. The patient had been diagnosed with chronic hepatitis C (Stage 6 of the Knodell classification based on liver biopsy) 10 years earlier. She had refused treatment and was reluctant to attend follow-up visits. One year before admission, biochemical markers (Fibrotest and Actitest) indicated severe fibrosis (A3-A4) and necroinflammatory activity (A3). Polymerase chain reaction tests showed that the patient was infected with HCV of genotype 1. The patient again refused treatment. She had a long history of hypertension more or less controlled by treatment. A consultant neurologist reexamined and found gait problems, postural instability with retropulsion, hypertonia involving all four limbs but most severe in the legs, and an absence of rest tremor. The neurologist reported generalized apraxia, no real cognitive impairment, and a Mini-Mental State Examination score of 29 of 30. She confirmed the diagnosis of VP. Cryoglobulinemia (type III) was detected. This is the first description of a case of VP associated with mixed HCV-related cryoglobulinemia. A causal effect is possible in this case. Disease of the small arteries and arterioles that penetrate the brain cortex and reach the underlying structures of the white and deep gray matter, such as the basal ganglia, are the primary cause of approximately one third of symptomatic strokes.8 Arteriolosclerosis probably affected these small vessels in our patient, who, like most patients with VP, had hypertension,3-5 but because few patients with hypertension develop parkinsonism, another determinant must also have been involved. We suspect that cryoglobulinemia may have played a role by increasing the burden on these small vessels affected by arteriolosclerosis. A previous study found9 that 40% of patients with VP had anticardiolipin antibodies (ACLA), which are associated with hypercoagulable states and stroke risk, but found no difference in vascular risk factors, such as hypertension, between ACLA-positive and -negative patients. Thus, as proposed in previous studies1, 3-5, 9 we suggest that a more-precise definition of the relationship between diseases of the small vessels in the brain and other conditions, such as HCV infection, is required. In particular, it would appear to be worthwhile to test patients with VP for HCV infection and cryoglobulinemia. Financial Disclosure: None. Author Contributions: All authors were involved in the analysis and interpretation of clinical data and the preparation of the manuscript. Sponsor's Role: None.