Focal seizures during adrenocorticotropic hormone therapy in a school-aged boy: a case report.

BACKGROUND: Adrenocorticotropic hormone therapy for infantile spasms, including West syndrome, has been previously reported to induce seizures. We present the findings for a school-aged child with epilepsy who developed new focal seizures during adrenocorticotropic hormone therapy. CASE PRESENTATION: The Japanese patient had posttraumatic epilepsy and developed intractable focal seizures at the age of 13 years. Adrenocorticotropic hormone therapy was administered when the patient was 14 years of age. On day 10 of treatment, he developed new focal seizures, which were characterized by left arm contractions followed by movements of touching things with his right hand and writhing and rocking his body left and right and back and forth as automatisms. The focal seizures clustered for 40 minutes and disappeared after suppository administration of 10 mg diazepam. These focal seizures did not reoccur after more than 2 years of follow-up. CONCLUSION: Adrenocorticotropic hormone-induced seizures can occur in children older than previously reported, and can occur in children with intractable seizures other than epileptic spasms.

Reversible splenial lesions during febrile illness with or without white matter lesions.

OBJECTIVE: Reversible splenium lesions during febrile illness (RESLEF) are found in a spectrum. There are two types of corpus callosum (CC) lesions: CC-only type, with limited lesions and the CC (+) type, with extensive white-matter lesions. This retrospective study aimed to describe the differences in clinical findings between CC-only and CC (+) lesions and the association between onset age and clinico-radiological features in RESLEF. METHODS: Fifty-two episodes of CC-only or CC (+) lesions accompanied by neurological symptoms, e.g., seizures, delirious behavior (DB), and disturbance of consciousness (DC), from January 2008 to October 2019 were included. We analyzed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography findings, therapy, and prognosis. RESULTS: The rate of DC in the CC (+) was significantly higher than that in the CC-only group (5/6 [83%] vs 7/46 [15%]; p = 0.0016). The median number of seizures in the CC (+) was also significantly higher than that in the CC-only group (4 [0-7] vs 0 [0-7]; p = 0.034). Further, in RESLEF, the median onset age (months) in the seizure was significantly lower than that in the no-seizure group (39 [12-74] vs 83 [28-174]; p = 0.0007). The median onset age (months) in the DB was significantly higher than that in the no-DB group (74.5 [26-174] vs 28 [12-139]; p = 0.003). CONCLUSIONS: In RESLEF, CC (+) is a more severe neurological symptom than CC-only. Furthermore, the onset age is related to the type of neurological symptoms that appear.

Treatment outcomes for infantile spasms in Japanese children with Down syndrome.

BACKGROUND: The aim of this study was to assess the treatment response to conventional antiepileptic drugs and low-dose adrenocorticotropic hormone therapy for infantile spasms in children with Down syndrome. METHODS: We retrospectively investigated the response and relapse rates, electroencephalography findings, patient characteristics during drug withdrawal, and developmental outcome in 10 children with Down syndrome treated for infantile spasms in our hospital. RESULTS: All patients showed cessation of infantile spasms and achieved electroencephalographic normalization. Spasm relapse occurred in one of 10 patients (10%). Antiepileptic drugs have been withdrawn for seven of 10 patients (70%), none of whom have experienced seizure relapse since drug withdrawal. The median developmental quotient (n = 8) was 20.5, which shows that the developmental outcome was unfavorable. Low-dose adrenocorticotropic hormone therapy achieved a low seizure remission rate of 28.6%. CONCLUSIONS: Elucidation of the optimal treatment for infantile spasms in children with Down syndrome is needed to reduce the duration of infantile spasms and improve the developmental outcome.

Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia.

BACKGROUND: Rapid-onset dystonia-parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms. CASE REPORT: We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified. DISCUSSION: This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.

Acute encephalopathy in children with tuberous sclerosis complex.

OBJECTIVE: We examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC). METHODS: The clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals. RESULTS: Of the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE. SIGNIFICANCE: AE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

Clinical findings in patients with febrile seizure after 5 years of age: A retrospective study.

OBJECTIVE: Febrile seizures (FSs) typically occur in infants and children between 6 and 60 months of age. Rarely, FS can occur in late childhood (late FS [LFS]; >5 years of age); however, the clinical features of LFS remain unclear. We aimed to clarify the clinical features of LFS. METHODS: We retrospectively analyzed data from patients with LFS who visited Hirakata City Hospital between January 2004 and December 2014. We defined LFS as a seizure accompanied by fever (temperature ≥38 °C) occurring after 5 years of age, without a central nervous system infection. RESULTS: A total of 505 patients (349 boys, 156 girls: 5-14 years old) were included. A history of FS before 60 months of age was observed in 319 of 460 patients (69.3%) with sufficient information about previous FS history among the 505 patients enrolled. LFS was more likely to occur in males (69.1%). Seizure duration was ≤15 min in 87.4% of cases. A family history of FS in first-degree relatives was observed in 103/327 cases (31.5%). Among LFS cases, 45% occurred at 5 years of age, and 92.1% experienced only one seizure after 5 years of age. The number of seizure episodes gradually lessened with age, decreasing drastically to 5.6% of cases older than 9 years. CONCLUSIONS: Our findings suggest that sex differences, seizure duration, and family history were similar for LFS and FS. Over 90% patients with LFS experienced no recurrence after 5 years of age. Further study is needed to verify the recurrence rate of LFS.

Acetaminophen and Febrile Seizure Recurrences During the Same Fever Episode.

OBJECTIVES: To confirm the safety of using acetaminophen for febrile seizures (FSs) and to assess its efficacy in preventing FS recurrence during the same fever episode. METHODS: In this single-center, prospective, open, randomized controlled study, we included children and infants (age range: 6-60 months) with FSs who visited our hospital between May 1, 2015, and April 30, 2017. The effectiveness of acetaminophen was examined by comparing the recurrence rates of patients in whom rectal acetaminophen (10 mg/kg) was administered every 6 hours until 24 hours after the first convulsion (if the fever remained >38.0°C) to the rates of patients in whom no antipyretics were administered. No placebo was administered to controls. The primary outcome measure was FS recurrence during the same fever episode. RESULTS: We evaluated 423 patients; of these, 219 were in the rectal acetaminophen group, and 204 were in the no antipyretics group. In the univariate analysis, the FS recurrence rate was significantly lower in the rectal acetaminophen group (9.1%) than in the no antipyretics group (23.5%; P < .001). Among the variables in the final multiple logistic regression analysis, rectal acetaminophen use was the largest contributor to the prevention of FS recurrence during the same fever episode (odds ratio: 5.6; 95% confidence interval: 2.3-13.3). CONCLUSIONS: Acetaminophen is a safe antipyretic against FSs and has the potential to prevent FS recurrence during the same fever episode.

Prognostic factors in the early phase of acute encephalopathy.

BACKGROUND: Neurological sequelae occur in 40% of patients with acute encephalopathy (AE). The early prediction of poor outcomes is critical to the initiation of appropriate treatment. The aim of the present study was therefore to elucidate prognostic factors that can be quickly and feasibly evaluated on hospital admission in patients with AE. METHODS: We analyzed data from 51 AE patients admitted to Hirakata City Hospital between January 2005 and December 2014. Age at onset, sex, underlying disease, status epilepticus (SE), presence of benzodiazepine-resistant SE (BZD-resistant SE), and basic blood serum parameters on admission were evaluated in relation to each patient's outcome. RESULTS: On univariate analysis age at onset, BZD-resistant SE, and serum aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, and platelet count varied significantly according to outcome. On multivariate analysis age at onset (≤21 months), presence of BZD-resistant SE, and AST (≥46 IU/L) were identified as independent variables associated with poor outcome. CONCLUSION: Age at onset, presence of BZD-resistant SE, and AST are associated with a poor prognosis in AE.

The efficacy of adrenocorticotropic hormone in a girl with anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Immunomodulatory therapy has shown some therapeutic benefits in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. In this report, we describe the use of adrenocorticotropic hormone (ACTH) immunotherapy with good outcome in a patient with anti-NMDAR encephalitis. SUBJECT AND METHODS: A 4-year-old girl developed convulsions in her right arm and leg without impaired consciousness. These convulsions occurred frequently in clusters of 10-20 events of 10-20 s duration. She was admitted to our hospital on the 6th day following her initial series of convulsions. Flaccid paralysis of the right hand and leg was also found. Interictal electroencephalography showed high-amplitude slow waves. No abnormal findings were shown on MRI. 99mTc-ECD brain SPECT on the 14th day showed hyperperfusion in the left hemisphere, including the left basal ganglia. The convulsions ceased following the oral administration of valproic acid on the 10th day; however, paralysis associated with choreic dyskinesia of the right arm and leg remained. ACTH immunotherapy was then performed on the 15th day. We identified the presence of N-methyl-D-aspartate receptor antibody in CSF samples taken on the 6th day. After ACTH therapy, the patient fully recovered from the paralysis associated with choreic dyskinesia of the right arm and leg. She has not had a relapse and has not required medication for over a year. CONCLUSION: ACTH immunotherapy may be a useful treatment option for patients with anti-NMDAR encephalitis, although further evaluation is required.

Post-vaccination MDEM associated with MOG antibody in a subclinical Chlamydia infected boy.

The mechanism of post-vaccination acute disseminated encephalomyelitis (ADEM) has been hypothesized as resulting from vaccination-injected antigens cross-reacting with myelin components, however, a precise etiology has been uncertain. In this report, we describe the case of a 6-year-old Japanese boy who had multiphasic disseminated encephalomyelitis (MDEM), and was positive for both anti-myelin oligodendrocyte glycoprotein (MOG) antibodies and Chlamydophila pneumoniae antibodies. After vaccinations that were the second one for measles and rubella, and the booster immunization for Japanese encephalitis, the patient presented with fever, headache, vomiting, and a change in personality. He was treated with a high-dose of intravenous methylprednisolone in the diagnosis of ADEM. However, these symptoms recurred with different magnetic resonance imaging lesion, and he was diagnosed as MDEM. Retrospective testing for pathogens revealed C. pneumoniae IgM and IgG antibodies, and it was considered that he was infected with C. pneumoniae subclinically. The patient's serum indicated a positive response for the anti-MOG antibody from the onset of the ADEM diagnosis and in all recurrent episodes. Chlamydia species infection has been known to play a role in demyelinating diseases. It is also known that the anti-MOG antibody may be present but not exhibit its pathogenesis in the absence of a cell-mediated inflammatory response; however, the precise mechanism of action of the anti-MOG antibodies is not yet determined. We propose the possibility that post-vaccination demyelinating disease may result from the synergistic effects of a preceding anti-MOG antibody, possibly produced in response to a subclinical Chlamydia species infection.

Targeted temperature management for acute encephalopathy in a Japanese secondary emergency medical care hospital.

BACKGROUND: The goals of this study, conducted in our secondary emergency care hospital, were to assess the effectiveness of targeted temperature management (TTM) for acute encephalopathy secondary to status epilepticus and to consider appropriate adaptations for use of TTM in this setting. METHODS: Medical records of patients admitted with acute encephalopathy to Hirakata City Hospital between January 2010 and December 2014 were retrospectively reviewed. Cases treated with TTM (36 °C) and methylprednisolone pulse (MP) therapy (TTM/MP) were compared with those treated with conventional MP regarding clinical courses and outcomes. RESULTS: In total, 20 children were retrospectively enrolled. In the TTM/MP group (10 cases) all survived intact. In the MP group (10 cases), 4 cases were left with neurological sequelae. Furthermore, in the TTM/MP group, the body temperature dropped more quickly. For pediatricians in this secondary emergency hospital, implementing the body temperature management system was not difficult. There were no complications caused by hypothermia. DISCUSSION: Use of TTM as the initial treatment for acute encephalopathy in the early-onset stage is possible in a secondary emergency care hospital. However, some acute encephalopathy cases are the so-called fulminant type; DIC or shock develops soon after onset and so it is sometimes difficult to introduce TTM. Fulminant-type patients should be transported to tertiary emergency care hospitals. Secondary emergency care hospitals must carefully select cases for TTM, keeping the possibility of transport to a tertiary emergency hospital in mind at all times.

Parents'opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood.

Objective: Patients with childhood-onset epilepsy often need continued epilepsy treatment into adulthood. We investigated parents' opinions of the changes in their children's epilepsy treatment during the transition from childhood to adulthood using questionnaires and formulated agendas to build the appropriate medical treatment system for epilepsy. Methods: We distributed questionnaires to parents of patients with epilepsy who were 12 to 18 years old. Results: We distributed 176 questionnaires, and analyzed 79 (45%) questionnaires. Most parents (59%) wanted their child to continue treatment for epilepsy in the pediatrics department because of confidence in the current treatment environment. Most parents (73%) were anxious about their child not being treated in the pediatrics department during future epilepsy medical treatments because of concerns about whether a proper handover from the pediatrics department to other departments is possible. No parent was recommended the departmental transition by the primary pediatrician to other courses for future epilepsy treatment, while 19% of par-ents had a sense of incongruity regarding epilepsy treatment at the current pediatrics department. Parents who were anxious about future epilepsy treatments had significantly fewer general-school students than parents without anxiety. In addition, their children had more seizures than children of parents who were not anxious. Furthermore, they wanted their child to continue treatment for epilepsy in the pediatrics department more than the parents without anxiety. Conclusions: Approximately 70% of the parents were anxious about obtaining future epilepsy treatment in clinical departments other than the pediatrics department. To build a satisfactory medical treatment system for patients with epilepsy having different backgrounds and requiring continued treatment in adulthood, it is important to create a cooperating network consisting of pediatricians, neurologists, neurosurgeons, psychiatrists, and epileptologists.

A child with acute encephalopathy associated with quadruple viral infection.

UNLABELLED: Pediatric acute encephalopathy (AE) was sometimes attributed to virus infection. However, viral infection does not always result in AE. The risk factors for developing infantile AE upon virus infection remain to be determined. Here, we report an infant with AE co-infected with human herpesvirus-6 (HHV-6) and three picornaviruses, including coxsackievirus A6 (CVA6), Enterovirus D68 (EV-D68), and human parechovirus (HPeV). EV-D68 was vertically transmitted to the infant from his mother. CVA6 and HPeV were likely transmitted to the infant at the nursery school. HHV-6 might be re-activated in the patient. It remained undetermined, which pathogen played the central role in the AE pathogenesis. However, active, simultaneous infection of four viruses should have evoked the cytokine storm, leading to the pathogenesis of AE. CONCLUSION: an infant case with active quadruple infection of potentially AE-causing viruses was seldom reported partly because systematic nucleic acid-based laboratory tests on picornaviruses were not common. We propose that simultaneous viral infection may serve as a risk factor for the development of AE.

Acute abdominal pain as the only symptom of a thoracic demyelinating lesion in multiple sclerosis.

Multiple sclerosis (MS) is a syndrome characterized by complex neurological symptoms resulting from demyelinating lesions in the central nervous system. We report a child with a relapse of MS whose only presenting symptom was severe abdominal pain. Dysfunctional intestinal mobility was assessed by abdominal computed tomography. Findings resembled paralytic ileus resulting from peritonitis. However, the patient demonstrated no other symptoms of peritonitis. A T2-weighted magnetic resonance image revealed a new demyelinating lesion localized to thoracic segments T4-T12. The lesion presumably affected autonomic efferents involved in intestinal mobility. Treatment with a pulse of methylprednisolone reduced both abdominal pain and lesion size. To our knowledge, this is the first reported case of a pediatric MS patient with a demyelinating lesion associated with an autonomic symptom of altered intestinal mobility in the absence of neurological symptoms. This atypical presentation of MS highlights the need for physicians' vigilance when treating this patient population.

Differential diagnosis of delirious behavior in children with influenza.

Delirious behavior (DB) in children infected with influenza virus is an important symptom associated with encephalopathy. As children with influenza-associated DB with encephalopathy may require therapy whereas children with influenza-associated DB without encephalopathy do not, distinguishing between these conditions is essential. To clarify these differences and identify the most common features of acute encephalopathy, we retrospectively reviewed the clinical course, laboratory data, magnetic resonance imaging (MRI) and electroencephalography (EEG) findings, therapy, and prognosis of 48 children with influenza exhibiting DB. Of the 48 children, 37 and 11 were diagnosed with influenza A and B, respectively. Moreover, 40 were diagnosed with DB without encephalopathy (DBNE group) and 8, with DB with encephalopathy (DBE group). Reversible splenial lesion (RESLE) was detected in 7 patients in the DBNE group, mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in 2 patients, and a mild form of acute encephalopathy with biphasic seizures and late reduced diffusion in 1 patient in the DBE group. Serum sodium levels <136mEq/L were observed in 28 cases. Disturbance of consciousness was observed in 25 cases, seizure in 20, and slow waves on EEG in 22. Methylprednisolone pulse therapy was administered in 8 cases. No cases of neurological sequelae were observed. Although most of the clinico-radiological features of the DBNE and DBE groups did not differ substantially, marked differences were observed in the age at onset, initial neurological symptoms, duration of DB, rate of seizure, and slowing of background activity on EEG. These differences should be considered when distinguishing between DBNE and DBE in children.

Serum N-Terminal Pro-B-Type Natriuretic Peptide (NTproBNP) Levels Are Elevated During the Acute Phase of Acute Encephalopathy-Associated Virus Infection.

Acute virus-associated encephalopathy induces seizures. Serum N-terminal pro-B-type natriuretic peptide (NTproBNP) levels are elevated following febrile and afebrile seizures. However, the role of NTproBNP in acute virus-associated encephalopathy pathology is unknown. We enrolled 10 patients with acute virus-associated encephalopathy and convulsions (E group: 7 boys, 3 girls; median age, 3.10 ± 1.92 years) and 130 patients with febrile seizure (FS group: 80 boys, 50 girls; median age, 3.23 ± 2.44 years). The E group had significantly higher NTproBNP levels (345 ± 141 pg/mL) compared with the FS group (166 ± 228 pg/mL) (P < .0005). Furthermore, subjects with prolonged seizure within the E group had significantly higher NTproBNP levels (303 ± 107 pg/mL) compared with subjects with prolonged seizure within the FS group (134 ± 100 pg/mL) (P < .005). Our findings suggest that serum NTproBNP levels are increased during the acute phase of acute virus-associated encephalopathy associated with convulsion.

ACTH therapy on intractable epilepsy in Hemiconvulsion-Hemiplegia-Epilepsy syndrome.

INTRODUCTION: In the chronic phase of Hemiconvulsion-Hemiplegia-Epilepsy (HHE) syndrome, developing epilepsy may be intractable. Herein, we report a case where adrenocorticotropic hormone (ACTH) ceased an intractable habitual partial seizure in a patient with HHE syndrome. CASE REPORT: A developmentally normal one-year-old girl presented with left focal motor status epilepticus in the clinical course of rotavirus infection. She was diagnosed with HH syndrome. At 4 months after status epilepticus, she developed partial seizures that occurred daily, and which resulted in a stooped posture, head rotation to the right, and contraction of both upper limbs predominantly in the left arm. At this time, she was diagnosed with idiopathic HHE syndrome. Her seizures were not reduced by sodium valproate, clonazepam, clobazam, zonisamide, phenytoin, phenobarbital, topiramate, lamotrigine, or liposteroid. At the age of 7, ACTH therapy was performed. On the 10th day of ACTH therapy, the habitual seizure was ceased. However, partial seizures characterized by left arm contraction then developed. Treatment with 350 mg/day lamotrigine prevented this emerging seizure. She has been free of both seizure types for more than one year, with no serious adverse effects of ACTH therapy. CONCLUSION: We suggest that ACTH therapy may be useful for patients with HHE, although further studies are required.

Overlapping MERS and mild AESD caused by HHV-6 infection.

We report the case of an overlapping encephalopathy syndrome consisting of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) and a mild form of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) caused by human herpesvirus-6. A previously healthy 17-month-old girl was admitted to our hospital as a precaution because of seizures that had developed more than 25 hours (h) after fever. Brain diffusion-weighted images (DWI) showed high signal intensity in the central splenial region on Day 2. She regained consciousness 16 h after the second seizure. On Day 6, she had a secondary cluster of partial seizures. DWI showed resolution of the splenial lesion and revealed reduced diffusion in the fronto-subcortical white matter. She regained consciousness 36 h after the secondary cluster of seizures without any sequelae. A third DWI performed on Day 15 showed that the fronto-subcortical white matter lesions had completely disappeared. Based on the clinicoradiological findings, we diagnosed the patient with overlapping MERS and mild AESD. Our case, together with previous reports, suggests that patients can develop combined encephalopathy syndromes as a phenotype. Many encephalopathy syndromes have been established and classified; however, some may not present as independent syndromes.

Delirious behavior or mild reduction of consciousness mimicking influenza-associated encephalopathy.

BACKGROUND: During the A/H1N1 pandemic, patients suffered from impaired consciousness. They were suspected of or diagnosed as having influenza-associated encephalopathy (IAE) in an emergency situation. Their symptoms resembled those of a recently described 'unique clinical group', which were reported to have a favorable prognosis. METHODS: We retrospectively examined 46 patients and divided them into two groups. Group IC contained the 26 patients with persisting impaired consciousness. The remainder of the patients were categorized into group R, consisting of patients with only neurological symptoms without impaired consciousness. RESULTS: Male predominance (22 male/four female) was noted in group IC. Patient age ranged from 5 to 12 years old (mean ± SD, 7.7 ± 2.3 years). Impaired consciousness such as delirious behavior or mild reduction of consciousness lasted continuously or intermittently from 5 min to 2.5 days. On electroencephalogram, semi-rhythmic high-voltage slow waves in the parieto-occipital regions and diffuse high-voltage slow waves were observed in eight and in two patients, respectively. In group R, there was no gender predominance. Patient age ranged from 1 to 9 years old (mean ± SD, 4.1 ± 2.5 years). All group R patients were clinically diagnosed with febrile seizure. CONCLUSIONS: Some of the characteristics in group IC resembled those of the unique clinical group, and are part of a continuous clinical spectrum. Some patients may have favorable outcome without specific treatment.