Ehlers-Danlos syndrome and small fiber neuropathy

Dell'Aversana D, Provitera V, Trinchillo A, Masciarelli F, Tozza S, Caporaso G, Vitale F, Borreca I, Areniello AR, Ciccarelli G, Esposito G, Iodice R, Dubbioso R, Manganelli F, Santoro L, Castori M, Nolano M. Distinct sensory and autonomic involvement in hypermobile Ehlers-Danlos syndrome compared with idiopathic small fiber neuropathy: a multimodal study. Sci Rep. 2026 Jul 3. doi: 10.1038/s41598-026-60461-6. Epub ahead of print. PMID: 42399338.

Abstract

Hypermobile Ehlers-Danlos syndrome (hEDS), frequently presents with pain and autonomic symptoms suggestive of small fiber neuropathy (SFN). However, systematic comparisons between hEDS and idiopathic SFN (iSFN) using combined clinical, functional, and morphological approaches are lacking. We prospectively studied a population of SFN patients who also fulfilled the 2017 criteria for hEDS (hEDS/SFN) and compared them with a group of iSFN patients of similar age. All underwent SFN-Symptoms Inventory Questionnaire (SFN-SIQ), Douleur Neuropathique 4 (DN4), and the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaires, quantitative sensory testing (QST), autonomic testing (cardiovascular reflexes, sympathetic skin response, dynamic sweat test), and skin biopsy from leg, thigh, and fingertip. Clinical, morphological and functional data were compared with our normative dataset and between the two patient groups. 35 hEDS/SFN and 38 iSFN patients were included in the study. hEDS/SFN patients had earlier symptom onset (19.5 ± 5.9 years vs. 35.2 ± 8.7 years, p < 0.001), more generalized distribution, and higher COMPASS-31 scores (54.3 ± 16.9 vs. 33.9 ± 19.4 p < 0.01), particularly in orthostatic intolerance, gastrointestinal, and urinary domains. Postural Orthostatic Tachycardia Syndrome (POTS) was present in half of hEDS/SFN patients while it was not found in iSFN (51.5% vs. 0.0%). Skin biopsy revealed similar intraepidermal nerve fiber loss in both groups, but hEDS had greater autonomic fiber loss (p < 0.05). Small fiber involvement in hEDS is characterized by earlier onset, more generalized pain and severe autonomic symptoms, and higher autonomic morpho-functional impairment compared with iSFN. Systematic autonomic assessment and targeted management should be considered in this population.

Novak P, Systrom DM, Marciano SP, Witte A, Warren A, Felsenstein D, Giannetti MP, Hamilton MJ, Nicoloro-SantaBarbara J, Castells M, Farhad K, Pilgrim DM, Mullally WJ, Fishman MC, Milunsky JM, Milunsky A, Krier J. Hypermobile Ehlers-Danlos Syndrome: Cerebrovascular, Autonomic and Neuropathic Features. Am J Med Open. 2025 Jul 18;14:100111. doi: 10.1016/j.ajmo.2025.100111. PMID: 40843452; PMCID: PMC12365377.

Abstract

Background: Hypermobile Ehlers-Danlos syndrome (hEDS) affects multiple systems, but comprehensive evaluations of a larger sample of hEDS patients are lacking. The objective of this study was to describe cerebrovascular, autonomic, and neuropathic features of hEDS.

Methods: This retrospective case-control study was conducted at Brigham and Women's Faulkner Hospital between 2016-2023. Data from hEDS patients who completed autonomic testing and skin biopsies were analyzed. Outcome measures include validated surveys (Survey of Autonomic Functions, Neuropathy Total Symptom Score-6 (SAS)) and autonomic function testing (Valsalva maneuver, deep breathing, head-up tilt and sudomotor), cerebrovascular (cerebral blood flow velocity (CBFv) in the middle cerebral artery), respiratory (capnography), and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/ autoimmune markers.

Results: Total 270 hEDS patients were analyzed and compared to 29 healthy controls. Common hEDS complaints (prevalence > 90% ) were orthostatic sudomotor, vasomotor, gastrointestinal, and pain. Orthostatic cerebral blood flow velocity was reduced in 79% of hEDS and correlated with orthostatic dizziness. The head-up tilt test revealed postural tachycardia syndrome (prevalence 33%), hypocapnic cerebral hypoperfusion (22%), orthostatic cerebral hypoperfusion syndrome (18%), and neurogenic orthostatic hypotension (9%). Widespread but mild autonomic failure was present in 90% of hEDS patients on autonomic testing. Small fiber neuropathy using structural criteria was detected in 64%, and using combined structural and functional criteria in 82%.

Conclusions: This study provided evidence of cerebrovascular dysregulation with reduced orthostatic cerebral blood flow velocity associated with symptoms of cerebral hypoperfusion, frequent small fiber neuropathy, and widespread but mild autonomic failure in hEDS.

Igharo D, Thiel JC, Rolke R, Akkaya M, Weis J, Katona I, Schulz JB, Maier A. Skin biopsy reveals generalized small fibre neuropathy in hypermobile Ehlers-Danlos syndromes. Eur J Neurol. 2023 Mar;30(3):719-728. doi: 10.1111/ene.15649. Epub 2022 Dec 13. PMID: 36437696.

Abstract

Background and purpose: Ehlers-Danlos syndromes are hereditary disorders of connective tissue that are characterized by joint hypermobility, skin hyperextensibility and tissue fragility. The most common subtype is the hypermobile type. In addition to symptoms of small fibre neuropathy (SFN) due to damage to the small peripheral nerve fibres, with degeneration of the distal nerve endings, autonomic disorders such as postural tachycardia syndrome (PoTS) are frequently reported features in patients with hypermobile Ehlers-Danlos syndrome (hEDS). To date, the underlying pathophysiological mechanisms are still not completely understood.

Study purpose: To better understand pathophysiological mechanisms of small fiber neuropathy and autonomic neuropathy in hypermobile Ehlers-Danlos Syndromes.

Methods: We prospectively investigated 31 patients with hEDS compared to 31 healthy controls by using skin biopsy, quantitative sensory testing, tilt-table testing, the painDetect, Small Fibre Neuropathy Screening List and the COMPASS-31 (Composite Autonomic Symptom Score 31) questionnaire.

Results: Nineteen (61%) patients with hEDS were diagnosed with SFN, and 10 (32%) fulfilled the criteria for PoTS. Patients with hEDS had significantly higher heart rates than controls. According to quantitative sensory testing, these patients had generalized thermal and tactile hypesthesia. Skin biopsy revealed significantly reduced intraepithelial nerve fibre density proximally (thigh) and distally (lower leg) in patients compared to controls. This was consistent with various complaints of pain and sensory disturbances in both the proximal and distal body regions.

Conclusion: These results confirm histologically proven SFN as a common feature in patients with hEDS, revealing a generalized distribution of nerve fibre loss. Regarding the frequently reported autonomic and neuropathic dysfunctions, the findings support SFN as an important, but not the only, underlying pathomechanism.

See: https://childnervoussystem.blogspot.com/2016/10/ehlers-danlos-syndrome-linked-to-small.html

Great experiments 3

Lee HF, Chi CS, Tsai CR, Chen CH, Wang CC. Electroencephalographic features of patients with SCN1A-positive Dravet syndrome. Brain Dev. 2015 Jun;37(6):599-611. doi: 10.1016/j.braindev.2014.10.003. Epub 2014 Oct 27. PMID: 25459968.

Video EEG recording during HWBT (hot water bathing test) was performed after obtaining informed consent from the patients’ parents. After a 20-min routine EEG recording, the patient was requested to remove his or her clothing and then sit in chest above the level of the water. The initial water temperature was around 35–37 C depending on the patient’s preference. Hot water at a temperature of around 55–60 C was collected in a stainless wash basin. The water temperature of the bath tub was increased gradually by means of alternately scooping water out of the bath tub and transferring hot water from the wash basin to the bath tub to raise the water temperature up to a maximum of around 40 C. Simultaneously, water from the bath tub was intermittently poured onto the patient’s shoulders with a small bowl in order to elevate the patient’s body temperature. The patient’s axillary temperature and the water temperature were recorded simultaneously every 10 min during the course of the test. The procedure was discontinued immediately after seizure initiation. In cases where the patient exhibited a seizure during the test, he or she was taken out of the water, placed on a bed, gently dried with a towel, and seizure patterns were then recorded. If no seizure developed, the HWBT was ended after 30 min, and the final axillary and water temperatures were recorded.

Mytinger JR, Weisleder P. E. Steve Roach: Reflections From the Editor-In-Chief of Pediatric Neurology. Pediatr Neurol. 2021 Dec;125:58-60. doi: 10.1016/j.pediatrneurol.2021.09.006. PMID: 34715988.

What is the most chillingly inappropriate manuscript that was submitted during your term as the journal's editor?

One alarming manuscript summarized a study that attempted to verify the clinical observation that increased temperature can trigger seizures in children with Dravet syndrome by immersing children in a hot water bath designed to raise their body temperature to see if it would trigger a seizure. The children who experienced a seizure were then removed from the bath so the seizure could be filmed and characterized, with no stated plan for intervening should a prolonged seizure occur. All of this, naturally, without mention of an institutional review board approval!

(The Lee article is not necessarily the one referred to in the Mytinger article. I could not confirm.)

Pediatric headache: A comprehensive review

Wander A, Meena AK, Choudhary PK, Peer S, Singh R. Pediatric Headache: A Comprehensive Review. Ann Child Neurol. 2024;32(4):207-218.

Abstract

Pediatric headache is a common condition that often results in frequent outpatient visits. There are two broad etiological groups of headaches—primary and secondary headaches—with the former being more prevalent. Migraine, a type of primary headache, shares similarities with those experienced by adults, albeit with some variations in diagnostic criteria. The secondary causes of headache should be differentiated from the primary headaches with proper clinical evaluation and focussed investigations. The management of migraine focusses on lifestyle modifications, behavioral therapy, and pharmacotherapy for acute episodes and long-term preventive therapy. There are many novel promising treatment modalities. This review article provides an overview of pediatric headache epidemiology, classification, and pathophysiology and then elaborates on management and prevention strategies.

From the article:

1. Etiology

Headaches in children can be categorized into primary, where pain is a result of the headache condition itself, and secondary, where pain serves as a symptom of an underlying condition. Migraine and tension-type headaches are the most frequently encountered types of primary headaches in children. Cluster headache, a type of primary headache in children, exhibits similar characteristics to headaches in adults but is rare among young children. Upper respiratory tract infections are the commonest cause of secondary headaches that prompt emergency visits. Meningitis, hydrocephalus, and intracranial tumours are common etiologies of life-threatening headache in children. Frequently, no diagnosis can be reached despite an extensive evaluation. In a study involving 48,575 children aged 5 to 17 years who had headache disorders, about 19% were identified with primary headaches, 1.1% were diagnosed with secondary headaches, and 79.7% did not receive a formal diagnosis.

2. Pathophysiology

The pathophysiology of headaches is intricate, with genetic and environmental factors playing crucial roles in the development of migraine, tension-type headache, and cluster headache. However, identifying the specific genes involved has proven to be a challenging task. Familial hemiplegic migraine, which is linked to mutations in the calcium voltage-gated channel subunit alpha1 A (CACNA1A), ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2), and sodium voltage-gated channel alpha subunit 1 (SCN1A) genes, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with a notch receptor 3 (NOTCH3) gene mutation, stand out as the most extensively studied headache disorders with a genetic foundation.

The vascular theory of migraines, according to which migraine stems from blood vessel dilation and that the aura is a result of vasoconstriction, is now deemed invalid, as evidenced by magnetic resonance angiography studies. A typical migraine episode consists of four phases: the prodromal or premonitory phase, the aura phase, the headache phase, and the post-dromal phase. The premonitory phase is characterized by irritability, fatigue, difficulty in concentration, nausea, or pallor. Functional neuroimaging studies suggest involvement of the hypothalamus in the premonitory phase, as well as during the migraine attack phase. The migraine aura constitutes a reversible neurological phenomenon impacting approximately one-third of all migraine sufferers and occasionally overlapping with the headache phase. The underlying mechanism of this phase is thought to involve cortical spreading depolarization (CSD) across the cortex. CSD is marked by a brief excitation period, followed by a prolonged depression of cortical activity. Originating from the occipital lobes, it propagates anteriorly, dissipates at the central sulcus, and influences neurotransmitter levels, ionic balance, and blood flow. The headache phase is characterized by the activation of the trigeminocervical complex. Neuropeptides, particularly calcitonin gene-related peptide (CGRP), are involved in trigeminal activation and have emerged as a potential target for therapeutic interventions in migraine patients. 

The development of cluster headaches involves interactions among the trigemino-vascular pathway, trigeminal autonomic reflex, hypothalamus, and the neuropeptides CGRP and pituitary adenylate cyclase-activating polypeptide. In tension-type headaches, the pain is thought to stem from myofascial structures and is heightened by central sensitization mechanisms. This central sensitization involves an imbalance in neurotransmitters such as CGRP, nitric oxide, neurokinin-A, glutamate, substance-P, serotonin, and endogenous peptide systems...

Conclusion

Pediatric headache is a prevalent condition in children, leading to substantial morbidity and frequent healthcare visits. The primary culprits are often primary headaches and acute viral infections. The initial assessment is essential for identifying potential warning signs, excluding secondary or life-threatening causes of headaches, and minimizing unnecessary investigations. Migraine is the most significant and common type of headache in children and adolescents. Prompt acute management of migraines involves supportive care and analgesics, but there is a lack of clear evidence-based recommendations for preventive therapy in children, highlighting a need for further research in this area. Newer modalities including non-invasive neuro-simulation botulinum toxin and CGRP antagonists are promising and emerging therapies. 

Phenomenology and clinical relevance of minor neurological signs in child neurology

Magostini F, Paris G, Capuano A. Phenomenology and clinical relevance of minor neurological signs in child neurology and psychiatry. Front Neurol. 2026 May 8;17:1761780. doi: 10.3389/fneur.2026.1761780. PMID: 42180220; PMCID: PMC13193831.

Abstract

Minor Neurological Signs, also referred to as neurological soft signs, are subtle abnormalities detected during neurological examination that do not meet criteria for major focal deficits. They are increasingly considered indicators of variability in neurodevelopment, likely reflecting differences in sensorimotor integration and maturation of cortico–subcortical networks. This mini review summarizes current evidence on the phenomenology, neurobiological correlates, and clinical relevance of MNS in child neurology and psychiatry. MNS include motor features such as overflow movements, dysmetria, dysrhythmia, and mild alterations in coordination, tone, and balance. Their assessment relies on standardized, developmentally appropriate tools that support identification of distinct patterns of dysfunction. MNS are frequently reported in neurodevelopmental and psychiatric conditions. While not diagnostically specific, they have been associated with symptom severity and functional outcomes. Further longitudinal and integrative studies are needed to clarify their developmental trajectories, neurobiological mechanisms, and potential clinical utility.

From the article:

In line with the movement disorders classification and subsequent classification efforts in the field of minor neurological signs, we can identify the following phenomenological categories:

1) Hyperkinetic movement disorders: these are characterized by involuntary movements, primarily manifesting as tremors, choreiform movements, and dystonic postures.

a) Tremor: defined as a rhythmic, oscillatory movement of a body part, resulting from alternating or synchronous contractions of antagonist muscles, and may occur at rest, during posture, or during action.

b) Choreiform movements: frequently described as “dance-like” or “piano playing movements”, consist of brief, irregular, non-rhythmic, and unpredictable movements that flow randomly from one body part to another, predominantly affecting the distal extremities. These movements are not suppressible and are characterized by variability in timing, amplitude, and distribution.

c) Dystonia: characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures. These movements are typically patterned, twisting, and may be triggered or worsened by voluntary action.

2) Overflow movements: these refer to involuntary movements of body parts that are not necessary to perform a motor task effectively. Notable examples include contralateral motor overflow and mirror movements.

3) Dysmetria: this is identified as an inability to control the trajectory of purposeful movements, particularly concerning coordination of the extremities.

4) Miscellaneous disturbances: this category includes mild alterations in muscle tone, abnormalities in balance and gait (e.g., tandem gait), lateralization and dysrhythmia (an impairment of motor timing and of the ability to generate, maintain, or synchronize temporal sequences of movement, resulting in irregularity in rhythmic execution and coordination).

Although individually non-specific, these signs reflect variations in the organization and integration of distributed sensorimotor networks and are commonly observed within the spectrum of minor neurological signs...

The systematic observation of MNS provides clinically relevant information on the functional organization of developing neural systems involved in motor control and sensory integration. Rather than directly informing etiology, MNS can be understood as observable markers of variability in the organization and functioning of subcortical and cortico–subcortical systems. However, their clinical relevance is often underestimated and not always fully recognized during assessment, despite their potential to support early identification of risk in children who do not yet meet full diagnostic criteria but present emerging signs of neurodevelopmental vulnerability.

In the clinical context, MNS should be conceptualized as structured, domain-specific configurations of signs that support the identification of neurodevelopmental subgroups. MNS can be interpreted as intermediate phenotypes along a spectrum that includes, on one end, transient maturational variations and, on the other, conditions characterized by structural and persistent deficits, such as cerebral palsy.

The systematic assessment of MNS using standardized and specific tools is essential to clinical practice. Recognizing MNS as central components of neurodevelopmental assessment may improve early diagnosis, refine phenotypic stratification, and support the implementation of earlier and more tailored interventions in neurodevelopmental disorders.

Multiple genetic etiologies causing Dandy-Walker variant with microcephaly, epilepsy, and global developmental delay.

Zhang LB, Wu YY, Qiu DJ, Li WB, Ye ZL. Child Neurology: Multiple Genetic Etiologies Causing Dandy-Walker Variant With Microcephaly, Epilepsy, and Global Developmental Delay. Neurology. 2026 Apr 14;106(7):e214793. doi: 10.1212/WNL.0000000000214793. Epub 2026 Mar 6. PMID: 41791021.

Abstract

Dandy-Walker syndrome is typically characterized by near-complete cerebellar vermis agenesis, enlarged posterior fossa, and dilated fourth ventricle. By contrast, Dandy-Walker variant (DWv) shows milder features, typically characterized by partial agenesis of the cerebellar vermis, mild enlargement of the posterior fossa, and variable dilation of the fourth ventricle. Both conditions are usually associated with normal or enlarged head circumference. We report a 16-month-old girl presenting with congenital microcephaly, frequent seizures, and severe global developmental delay. Brain MRI revealed findings consistent with DWv, which did not explain the severity of her clinical symptoms or her microcephaly. Chromosomal microarray analysis revealed multiple regions of homozygosity on chromosome 11, indicating potential recessive inheritance; karyotype analysis and mitochondrial testing showed no clear etiology. Trio-based whole-exome sequencing identified a heterozygous variant (NM_021096.4:c.4891T>A/p.Phe1631Ile) in CACNA1I and a homozygous variant (NM_002335.4:c.1310C>T/p.Thr437Met) in LRP5. Variants in CACNA1I are associated with neurodevelopmental disorders, including epilepsy and developmental delay, while variants in LRP5 are linked to osteoporosis and microcephaly. Based on the clinical presentation and molecular findings, we hypothesize that both variants contributed to the patient's complex phenotype. This case highlights that in patients with unusually severe or atypical manifestations, the possibility of multiple genetic pathogenic contributions should be considered, and comprehensive genomic evaluation is essential for accurate diagnosis and management.

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

Cellucci T, Van Mater H, Graus F, Muscal E, Gallentine W, Klein-Gitelman MS, Benseler SM, Frankovich J, Gorman MP, Van Haren K, Dalmau J, Dale RC. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2020 Jan 17;7(2):e663. doi: 10.1212/NXI.0000000000000663. Erratum in: Neurol Neuroimmunol Neuroinflamm. 2020 Apr 15;7(4):e730. doi: 10.1212/NXI.0000000000000730. PMID: 31953309; PMCID: PMC7051207.

Abstract

Objective: Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.

Methods: A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.

Results: Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.

Conclusions: Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

Last American to use an iron lung dies

A 78-year-old Oklahoma woman who was diagnosed with polio as a child and was the last American to rely on an iron lung to live has died.

Martha Lillard found out she had the once-feared disease when she was 5 years old, which left her paralyzed from the neck down, and required her to use the machine to help her breathe while she slept.

Lillard contracted COVID-19 twice during the pandemic, which left her in the machine nearly 24 hours a day.

"They told her she wasn't supposed to live past 20 years old," her younger sister, Cindy McVey, told The Associated Press on Friday. "She had the enthusiasm and the drive to continue living and make the best of her life."

Despite having polio, Lillard was able to go to school two hours a day as a child, and she had tutors the rest of the time. She also used an intercom phone system that allowed her to interact with her teachers and classmates from home.

Lillard was even able to take road trips as a child because of a custom trailer that could accommodate the iron lung and her father making sure their hotels had wide enough doors for the machine.

An iron lung is a negative-pressure ventilator that helps a patient with paralyzed lung muscles breathe.

The disease once caused thousands of cases of paralysis in children during outbreaks each year in the first part of the 20th century before a vaccine became available in 1955.

By 1979, polio was considered eliminated in the U.S.

Later, Lillard was able to regain the use of her left arm and legs through therapy and was even able to drive for a time.

She lived independently for many years, even getting married earlier this year to a man from Egypt she corresponded with for two decades after he was able to obtain a visa.

"They were really soul mates," McVey said. "He's extremely brokenhearted."

Lillard, who wrote poetry and volunteered with the Humane Society, according to her sister, had just 25% lung capacity before she was diagnosed with COVID.

https://www.foxnews.com/health/last-american-use-iron-lung-dies-78-years-old-childhood-polio-diagnosis