Largest comparison between onset and relapses of acquired thrombotic thrombocytopenic purpura reveals severe neurological involvement and worse analytic parameters at debut.

It has been proposed that the onset of Acquired Thrombotic Thrombocytopenic Purpura (iTTP) is more severe than subsequent relapses; however, existing studies have limitations. We conducted a retrospective observational study to compare analytical and clinical severity of onset and relapse aTTP cases between 2012 and 2023. A total of 370 episodes of aTTP were analyzed, comprising 272 at initial diagnosis and 98 relapses. At onset, analytical parameters indicative of severity (low hemoglobin, low platelet count, and increased LDH) were significantly worse; patients had severe neurological symptoms (p<0.001) and ≥ 3 points in the TMA mortality score (p<0.001). In conclusion, the onset of aTTP is associated with worse analytical parameters and severe neurological involvement.

Neurological involvement in hematopoietic stem cell transplantation-associated thrombotic microangiopathy.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT). The understanding of TA-TMA pathophysiology has expanded in recent years. Dysregulation of the complement system is thought to cause endothelial injury and, consequently, microvascular thrombosis and tissue damage. TA-TMA can affect multiple organs, and each organ exhibits specific features of injury. Central nervous system (CNS) manifestations of TA-TMA include posterior reversible encephalopathy syndrome, seizures, and encephalopathy. The development of neurological dysfunction is associated with a significantly lower overall survival in patients with TA-TMA. However, there are currently no established histopathological or radiological criteria for the diagnosis of CNS TMA. Patients who receive total body irradiation (TBI), calcineurin inhibitors (CNI), and severe acute and chronic graft-versus-host disease (GVHD) are at a high risk of experiencing neurological complications related to TA-TMA and should be considered for directed TA-TMA therapy. However, the incidence and clinical manifestations of TA-TMA neurotoxicity remain unclear. Studies specifically examining the involvement of CNS in TMA syndromes are limited. In this review, we discuss clinical manifestations and imaging abnormalities in patients with nervous system involvement in TA-TMA. We summarize the mechanisms underlying TA-TMA and its neurological complications, including endothelial injury, evidence of complement activation, and treatment options for TA-TMA.

Case Report: a novel CYP27A1 gene variant in a patient with cerebrotendinous xanthomatosis with unusual clinical findings.

PURPOSE/AIM OF THE STUDY: Cerebrotendinous xanthomatosis is a disease with important clinical and molecular heterogeneity. CYP27A1 gene was described as the cause of these defects, with more than 50 mutations involved in the disease. The objective of this study was to carry out a genetic study and a clinical description of a patient with unusual clinical manifestation of the disease. MATERIALS AND METHODS: DNA sequencing was used for the evaluation of CYP27A1 exon sequences and their intron/exon boundaries. Copy number variants were calculated using a method based on depth of sequencing coverage. In addition, the potential effects of the missense variants were analyzed, and an in-silico protein modeling tool was used. Finally, a patient case description was performed in order to evaluate patient phenotype according to genetic results. RESULTS: Patient clinical features indicate the possible presence of a disease milder phenotype. When analyzing the CYP27A1 gene, patient presents a pathogenic variant (p.Arg474Trp) and a variant of unknown significance (p.Met130Ile) that causes a slight modification of the protein functional structure. This variant in homozygosis or double or compound heterozygosis together with other biallelic pathological mutations may be the cause of the clinical phenotype observed in the reported patient. CONCLUSIONS: Clinical manifestations of cerebrotendinous xanthomatosis are heterogeneous, and sometimes wrongly suggest the presence of other diseases. Some patients seem to present an "incomplete" phenotype, which could be redefined as a variant of the disease with further studies. The evaluation of new mutations allows for earlier diagnosis and greater effectiveness in its treatment.

Neurological involvement in children with hemolytic uremic syndrome.

Our objective was to establish the rate of neurological involvement in Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS) and describe the clinical presentation, management and outcome. A retrospective chart review of children aged ≤ 16 years with STEC-HUS in Children's Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit, and/or seizure activity. Data on clinical presentation, management, and outcome were collected. We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (11%). The most common presentation was seizures (73%). In the neurological group, 19 (86%) were treated with plasma exchange and/or eculizumab. Of the 21 surviving children with neurological involvement, 19 (91%) achieved a complete neurological recovery. A higher proportion of children in the neurological group had renal sequelae (27% vs. 12%, P = .031). One patient died from multi-organ failure.Conclusion: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 11%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 91%) and a low case-fatality rate (4.5%) in our cohort. What is Known: • HUS is associated with neurological involvement in up to 30% of cases. • Neurological involvement has been reported as predictor of poor outcome, with associated increased morbidity and mortality. What is New: • The incidence of neurological involvement in STEC-HUS is 11%. • Neurological involvement is associated with predominantly good long-term outcome (90%) and a reduced case-fatality rate (4.5%) compared to older reports.

An inter- and intra-rater agreement assessment of a novel classification of pyogenic spinal infections.

PURPOSE: Pola et al. described a clinical-radiological classification of pyogenic spinal infections (PSI) based on magnetic resonance imaging (MRI) features including vertebral destruction, soft tissue involvement, and epidural abscess, along with the neurological status. We performed an inter- and intra-observer agreement evaluation of this classification. METHODS: Complete MRI studies of 80 patients with PSI were selected and classified using the scheme described by Pola et al. by seven evaluators. After a four-week interval, all cases were presented to the same assessors in a random sequence for repeat assessment. We used the weighted kappa statistics (wκ) to establish the inter- and intra-observer agreement. RESULTS: The inter-observer agreement was substantial considering the main categories (wκ = 0.77; 0.71-0.82), but moderate considering the subtypes (wκ = 0.51; 0.45-0.58). The intra-observer agreement was substantial considering the main types (wκ = 0.65; 0.59-0.71), and moderate considering the subtypes (wκ = 0.58; 0.54-0.63). CONCLUSION: The agreement at the main type level indicates that this classification allows adequate communication and may be used in clinical practice; at the subtypes level, the agreement is only moderate.

Cerebrotendinous xanthomatosis without neurological involvement.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. METHODS: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. RESULTS: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. CONCLUSIONS: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Definitive pathognomonic signs and symptoms of paediatric neurological COVID-19 are still emerging.

Children with COVID-19 tend to show milder symptoms than adults during the pandemic, but growing evidence of neurological involvement has emerged. Some studies have reported neurological symptoms in children with COVID-19, which include multisystem inflammatory syndrome, a disease that shares some, but not all, of the characteristics of Kawasaki disease. This review presents, and discusses, the evidence to date. Our initial findings suggest that neurological manifestations can be considered to be the direct result of central nervous system viral invasion or post-infection immuno-mediated disease.

Behçet: the syndrome.

Behçet's syndrome (BS) is a systemic vasculitis characterized by a relapsing and remitting course. It can involve the skin, mucosa, joints, vessels (arteries and/or veins), eyes, and nervous and gastrointestinal systems, and so is referred to as a syndrome rather than as a unique and nosologically distinct condition. These involvements may present alone or co-exist in the same patient. Although all the possible combinations of the above-mentioned manifestations may occur, clusters of commonly co-existing involvements (also referred to as 'disease phenotypes') have been suggested, namely 'mucocutaneous and articular', 'peripheral vascular and extra-parenchymal neurological' and 'parenchymal neurological and ocular' phenotypes have been described. Patient-specific demographic and genetic features have been described as positively or negatively associated with specific disease phenotypes. This review will focus on the different clinical features of Behçet's syndrome, summarizing current evidence on the distinct disease manifestations as well as the major phenotypes.

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement.

BACKGROUND: Thrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC). METHODS: TMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab. RESULTS: The great clinical variability of brain injury in our cohort has led us to retrospectively build a "neurological score" useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI). CONCLUSIONS: A "neurological score" may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

[The neurological manifestations in 52 patients with primary Sjögren's syndrome].

Objective: To summarize the neurological manifestations in patients with primary Sjögren's syndrome (pSS). Methods: A total of 68 patients were diagnosed as pSS in neurology department of Peking Union Medical College Hospital from March 2014 to February 2018, among whom sixteen cases were excluded due to modified final diagnoses of primary neurological diseases. Therefore 52 pSS patients with neurological involvement were enrolled and retrospectively analyzed. They were divided into two groups as extensive group in which both central and peripheral nervous system were involved, non-extensive group in which either central or peripheral nervous system was involved. Results: Neurological manifestations were presented as primary symptoms in 98.1%(51/52) patients, while 35 had neurological involvement as their only extraglandular manifestations. Thirteen cases were in extensive group. The other 39 in non-extensive group including 22 cases with only peripheral nervous system involved and 17 cases with only single central nervous system involved. Compared to non-extensive group, the proportion of woman patients [13/13 vs.71.8% (28/39), P=0.047], serum IgG level [17.73(11.11,22.41)g/L vs. 11.49(9.58,13.40)g/L, P=0.017] and positive rates of oligoclonal band (OB) in cerebral spinal fluid (CSF) [7/13 vs. 22.6%(7/31), P=0.042)] were significantly higher in extensive involvement group. Conclusions: Neurological manifestations in pSS patients could be extensive, both central and peripheral nervous system might be associated. Female patients, high serum IgG level and positive OB in CSF are risk factors of extensive neurological involvement, suggesting that the immune system may be generally over-stimulated.

Extra-Renal manifestations of atypical hemolytic uremic syndrome in children.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a chronic disease characterized by thrombotic microangiopathy and a high risk of end-stage kidney disease. Dysregulation and/or excessive activation of the complement system results in thrombotic microangiopathy. Interest in extrarenal manifestations of aHUS is increasing. This study aimed to determine the clinical characteristics of patients with extrarenal manifestations of aHUS in childhood. METHODS: This study included 70 children with extrarenal manifestations of HUS from the national Turkish aHUS Registry. The demographics, clinical characteristics, genetic test results, all treatments, and renal/hematologic status of aHUS patients with extrarenal involvement were recorded. RESULTS: The most common extrarenal manifestation was neurological system involvement (n = 46 [27.2%]), followed by gastrointestinal (n = 20 [11.8%]), cardiovascular (n = 12 [7%]), and respiratory (n = 12 [7%]) involvement. The patients with neurological involvement had a higher mortality rate and a lower estimated glomerular filtration rate (eGFR) than the other patients at last follow-up. Eculizumab (with or without plasma exchange/plasma infusion) treatment increased the renal and hematologic recovery rates. CONCLUSIONS: The most common and serious extrarenal manifestation of aHUS is neurological involvement and treatment outcome findings presented herein are important to all relevant clinicians.

Focus on neuro-Behçet's disease: A review.

Behçet's disease (BD) is a multisystemic vasculitis disorder of almost unknown etiology, which involves small and large vessels and affects both veins and arteries. BD is characterized by recurrent oral aphthae (the main and most recurrent symptoms), genital ulcers, variable skin lesions, arthritis, uveitis, and thrombophlebitis. Other reported symptoms concern the involvement of the gastrointestinal and the central nervous system. Neuro-Behçet's disease (NBD) is one of the main causes of long-term morbidity and mortality, making its prompt recognition and treatment fundamental to attaining a better outcome. As pointed out by Kalra et al., there are definite consensus statements for BD, but less data are available for NBD. A multidisciplinary team of rheumatologists, dermatologists, ophthalmologists, neurologists, cardiovascular surgeons, and gastroenterologists, often led by rheumatologists, participate in the management of patients with BD and NBD.

Neurological manifestations of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune connective tissue disease affecting the exocrine glands, leading to damage of their structure and impairment of their function. In the course of pSS the internal organs may be involved and the symptoms may concern any system. Neurological disorders are one of the most common extraglandular manifestations of pSS. Available literature data estimate the prevalence of neurological symptoms as about 8.5-70% of patients diagnosed with pSS. The most common neurological complication of pSS is peripheral neuropathy, and in particular sensory polyneuropathy. Central nervous system involvement is much less common. There are also reports of various symptoms connected with damage to cranial nerves and the autonomic nervous system. A careful neurological evaluation, combined with neurophysiological tests, is recommended in patients with pSS. This review summarizes the neurological manifestations of pSS, their possible pathogenic mechanisms, diagnostic evaluation and potential treatment.

Neurological involvement in patients with acute/recent HIV-1 infection. A case-control study.

Primary HIV-1 infection is a relevant period for its virological and epidemiological consequences. Most patients present a symptomatic disease that can be potentially serious, but neurological involvement during primary HIV-1 infection has been poorly studied. The aim of this study was to describe the characteristics and outcomes of primary HIV-1 infection patients presenting neurological symptoms and to compare them with primary HIV-1 infection patients without neurological involvement. Retrospective case-control study (1:3) comparing primary HIV-1 infection patients with and without neurological involvement enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016. Matching criteria included age (±10 years), gender, year of diagnosis (±4 years), and Fiebig stage. The conditional logit model was used for comparisons. Fourteen out of 463 patients (3.02%) enrolled in the Acute/Recent Hospital Clinic PHI Cohort between 1997 and 2016 presented neurological symptoms. 28.5% of cases presented as meningitis and 71.5% as meningoencephalitis. Cerebrospinal fluid showed non-specific findings, including pleocytosis with lymphocyte predominance and increased protein levels. All cases required hospitalisation, whereas only 19% of the controls did. No other pathogen was identified in any case, but five patients initiated empirically antimicrobial treatment for other aetiologies until diagnosis was confirmed. CD4/CD8 ratio was significantly lower (p = 0.039) and plasmatic viral load significantly higher in the case group, compared to controls (p = 0.028). Risk factors, HIV-1 tropism, subtype distribution, and prescribed ART regimens were comparable between cases and controls. After 6 months on ART, 92% of cases had undetectable viral load, similar to controls, and CD4/CD8 ratio became also comparable between groups. All cases recovered rapidly with ART and were discharged without sequels. Neurological involvement during primary HIV-1 infection is unusual but serious, always requiring hospitalisation. Diagnosis is difficult because of the wide range of symptoms and similarities with other viral aetiologies. Neurological manifestations during primary HIV-1 infection are associated with a lower CD4/CD8 ratio and with a higher viral load than controls. Immediate ART initiation and rapid viral load decrease are required, allowing complete clinical recovery.

Hypertrophic pachymeningitis associated with cerebral spinal fluid hypovolemia as initial presentation of systemic lupus erythematous.

We report a case of a 61-year-old man with thickening of the dura mater associated with the presence of subdural collections as a consequence of cerebral spinal fluid hypovolemia (CSFH) and hypertrophic pachymeningitis (HP) as presentation of systemic lupus erythematous (SLE). The patient complained about fatigue, musculoskeletal pain, headache and skin lesions. In the laboratory tests minimal normocytic anemia, mild leukopenia, polyclonal hypergammaglobulinemia and antinuclear antibodies (ANA), anti-double-stranded DNA antibodies (dsDNA), antibodies against extractable nuclear antigens (ENA) type SSA-Ro, anti-Smith antigen antibodies (anti-Sm) and anti-ribonucleoprotein antibodies (anti-RNP) were detected. Cranial magnetic resonance imaging (MRI), with and without gadolinium enhancement, revealed generalized thickening of the dura mater more severe at the right parieto-occipital lobes with the presence of subdural collections. The patient was diagnosed with SLE associated both with CSFH and HP. A conservative treatment with prednisone 60 mg daily, mycophenolate mofetil (MMF) 1 g daily and hydroxychloroquine 200 mg twice a day was started with significant clinical and radiological improvement (almost complete resolution of the subdural collections and clear decrease of meningeal thickness). The authors emphasize that HP associated with CSFH in the context of SLE is a rare entity, which makes this case unique.

Effect of Infliximab on Chronic Progressive Neuro-Behçet's Disease: Influence of the Timing of Introduction on the Patient Outcome.

Objectives Chronic progressive neuro-Behcet's disease (CPNB) is characterized by progressive deterioration leading to disability. Methotrexate (MTX) has been shown to have beneficial effects on CPNB. However, while infliximab has been found to be effective for patients with inadequate responses to MTX, the appropriate timing for the introduction of infliximab remains unclear. We explored the effects of intervals before the introduction of infliximab on the functional outcome. Methods A retrospective analysis was performed for patients with CPNB who received infliximab and were followed up until October 2015. Functional disability was rated by the Steinbrocker functional classification as used in rheumatoid arthritis. Correlations between the outcomes and intervals before the introduction of infliximab were then analyzed by Spearman's rank correlation test. Patients Eleven patients with CPNB [8 men, 3 women, age 35.2±9.3 years old (mean±standard deviation)] who met the international classification criteria for Behcet's disease were included. Results All 11 patients had received MTX prior to infliximab. The intervals from the onset to the introduction of infliximab and the follow-up periods were 26.6±35.1 months and 65.2±43.6 months [mean±standard deviation], respectively. Among the 11 patients, 2 still showed progression after the introduction of infliximab. The functional disability grades after infliximab treatment were significantly correlated with the intervals from the onset of CPNB to the introduction of infliximab (r=0.6177, p=0.0476). Conclusion The results indicate that the delayed introduction of infliximab leads to irreversible functional disability in CPNB. Thus, it is recommended that infliximab be administered as soon as possible for CPNB patients with inadequate responses to MTX.

Large-vessel involvement in ANCA-associated vasculitis: A multicenter case-control study.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) primarily affects small vessels. Large-vessel involvement (LVI) is rare. We aimed to describe the characteristics of LVI, to identify associated risk factors, and to describe its therapeutic management. METHODS: This multicenter case-control (1:2) study included patients with AAV according to the ACR/EULAR classification and LVI as defined by the Chapel Hill nomenclature, together with controls matched for age, sex, and AAV type. RESULTS: We included 26 patients, 15 (58 %) of whom were men, with a mean age of 56.0 ± 17.1 years. The patients had granulomatosis with polyangiitis (n = 20), or microscopic polyangiitis (n = 6). The affected vessels included the aorta (n = 18; 69 %) supra-aortic trunks (n = 9; 35 %), lower-limb arteries (n = 5; 19 %), mesenteric arteries (n = 5; 19 %), renal arteries (n = 4; 15 %), and upper-limb arteries (n = 2; 8 %). Imaging showed wall thickening (n = 10; 38 %), perivascular inflammation (n = 8; 31 %), aneurysms (n = 5; 19 %), and stenosis (n = 4; 15 %). Comparisons with the control group revealed that LVI was significantly associated with neurological manifestations (OR=3.23 [95 % CI: 1.11-10.01, p = 0.03]), but not with cardiovascular risk factors (OR=0.70 [95 % CI: 0.23-2.21, p = 0.60]), or AAV relapse (OR=2.01 [95 % CI: 0.70-5.88, p = 0.16]). All patients received corticosteroids, in combination with an immunosuppressant in 24 (92 %), mostly cyclophosphamide (n = 10, 38 %) or rituximab (n = 9, 35 %). CONCLUSION: Regardless of distinctions based on vessel size, clinicians should consider LVI as a potential manifestation of AAV, with the aorta commonly affected. The risk of developing LVI appears to be greater for clinical phenotypes of AAV with neurological involvement. Standard AAV treatment can be used to manage LVI.

Guillain-Barre Syndrome as an Atypical Early Presentation of Adult-Onset Still's Disease: A Case Report.

Adult-onset Still's disease (AOSD) is a rare auto-inflammatory disorder with unknown pathophysiology. Although having a heterogeneous clinical spectrum, the major features of AOSD include fever, rash, and arthritis or arthralgia. Neurological involvement is rare in AOSD with aseptic meningitis being the most common presentation. Guillain-Barre syndrome (GBS) has never been reported as an early presentation of AOSD. Herein, we describe the case of a patient presenting with GBS and fever of unknown origin who was soon diagnosed with AOSD and improved with corticosteroid therapy.

Case Report: Infant-onset Degos disease with nervous system involvement and a literature review.

Degos disease also known as malignant atrophic papulosis (MAP), is an autoinflammatory disease that mainly affects small- to medium-sized arteries. Gastrointestinal and nervous system are most commonly affected systems. Herein, we reported a case of Degos disease with disease onset during infantile and had severe neurological involvement.

A Case Report of Neuro-Behçet Syndrome: Frequent Neurological Manifestations Concurrent With Life-Threatening Illnesses.

​​​​Behçet disease (BD) is a recurrent, multisystemic autoimmune vasculitis that affects both small and large vessels. A combination of neurological signs and symptoms in BD is called neuro-Behçet syndrome (NBS). We present the case of a 31-year-old male diagnosed with chronic progressive NBS who presented with multiple relapsing episodes concurrent with infective endocarditis due to intravenous drug abuse, drug-induced hepatitis, acute kidney injury, and septic shock that is not related to BD. Neurological relapsing episodes were treated with steroids azathioprine and colchicine. At the same time, concurrent illnesses were managed appropriately. Infective endocarditis needed valve replacement surgery, and sepsis was treated with selected antibiotics. Fortunately, the patient's brain images and laboratory investigation improved accordingly. On average, patients with parenchymal neuro-Behçet syndrome (P-NBS) have a poor prognosis; within 10 years of diagnosis, 50% of those patients are severely disabled as our patient who became aphasic and quadriplegic.