Neuralgic Amyotrophy

Complex MONDO:0017362 Pathograph 20 Show in embeddings browser Acquired Peripheral Neuropathy

Neuralgic amyotrophy is an immune-mediated multifocal peripheral neuropathy that begins with an abrupt attack of severe shoulder-girdle pain and is followed, as the pain subsides, by patchy weakness and wasting in the upper limb. It is a clinical diagnosis; ancillary testing serves mainly to exclude infectious or malignant causes. This entry covers the acquired, idiopathic form. Hereditary neuralgic amyotrophy, caused by SEPTIN9 duplication, is a separate MONDO concept with a different initiating lesion and is deliberately not folded in here. Three things about this disease are commonly got wrong, and the entry is organised around them. It is not rare. Incidence is about 1 per 1,000 individuals, an order of magnitude above the figure the older literature carried, and it is still frequently missed. It is not benign. The original descriptions emphasised spontaneous good recovery, but the majority of patients never achieve full recovery, and long-term consequences are the rule rather than the exception. Most importantly, the residual disability is not simply the axonal damage. Persisting symptoms are attributed mainly to reduced endurance in the affected nerves combined with an altered posture and movement pattern - not to the axon loss itself. That distinction is what makes scapular-coordination rehabilitation a mechanistically targeted treatment rather than generic supportive care, and it is why the entry carries a separate maladaptive-motor-pattern arm downstream of the nerve injury. The other development worth recording is structural. High-resolution ultrasound and MRI identified hourglass-like constrictions - focal narrowings with proximal and distal nerve thickening, involving the perineurium, with marked edema and a mononuclear infiltrate of CD8-positive T lymphocytes. Whether these are a distinct entity or a late stage of the same inflammatory process is genuinely unsettled, and is recorded as a controversy rather than resolved in the causal chain.

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6
Pathophys.
7
Phenotypes
1
Gaps
20
Pathograph
5
Medical Actions
16
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC
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Discussions and Knowledge Gaps

1
Are neuralgic amyotrophy, hourglass nerve constriction and nerve torsion different evolutions of one pathological process, or distinct entities that resemble each other?
CONTROVERSY hourglass_constriction_same_disease_or_not
Attached to
pathophysiology#Focal Nerve Constriction and Torsion pathophysiology#Multifocal Inflammatory Attack on Peripheral Nerve
This is stated as an open question in the review literature rather than a settled point, and it has direct consequences for this entry's structure. If they are one process, the constriction node belongs downstream of the inflammatory attack, which is how the pathograph currently draws it, and the ultrasound categories - swelling, swelling with incomplete constriction, swelling with complete constriction, fascicular entwinement - are stages of a continuum. If they are separate entities, that edge is wrong and the constriction cases are a different disease that happens to look similar. The node carries mechanism_confidence: PROVISIONAL for this reason - causal_link_type records directness, not confidence, so it is not the slot that expresses this. The practical stakes are not academic: the constriction subgroup has a poor prognosis without surgery and a good one with it, so which patients are considered to have "neuralgic amyotrophy" determines who gets referred.
Show evidence (2 references)
PMID:38248282 SUPPORT Human Clinical
"The pathophysiology of neuralgic amyotrophy, hourglass constriction and nerve torsion is still poorly understood, and a generic role of inflammation is proposed for all these conditions."
States that the shared mechanism is proposed rather than demonstrated, which is the basis for recording this as a controversy.
PMID:38248282 SUPPORT Human Clinical
"in some cases of NA, after a first phase characterized by nerve inflammation and swelling, in selected anatomical conditions, the process evolves into hourglass constriction or nerve torsion"
The continuum hypothesis in its explicit form, which is the reading the pathograph currently encodes.
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Pathophysiology

6
Multifactorial Susceptibility to Brachial Plexus Immune Attack
Mechanism confidence: Provisional
Neuralgic amyotrophy is not attributed to a single initiating lesion. Genetic, biomechanical and immunologic factors are all implicated, and it is this multifactorial etiology - rather than a lack of study - that limits the ability to predict or prevent the recurrences that are common in this disease. The biomechanical component is what is thought to localise an otherwise systemic immune event to particular nerves.
Downstream
Multifocal Inflammatory Attack on Peripheral Nerve
Show evidence (2 references)
PMID:26662794 SUPPORT Human Clinical
"Recurrences are common, yet the proposed multifactorial etiology, which includes genetic, biomechanical, and immunologic factors, limits our capacity to predict or prevent them."
States the three-component etiologic model and its practical consequence, which is why this node is marked provisional rather than established.
PMID:38248282 SUPPORT Human Clinical
"Autoimmune, genetic, infectious and mechanical processes are thought to be involved, but etiopathogenesis is still incompletely understood"
An independent review reaching the same multifactorial conclusion and stating explicitly that the etiopathogenesis is not settled.
Multifocal Inflammatory Attack on Peripheral Nerve
Mechanism confidence: Established
Brachial plexus biopsy in affected patients shows florid multifocal mononuclear inflammatory cell infiltrates, which is the direct histopathological basis for calling the disorder immune-mediated. The infiltrate in the constricted segments is composed of CD8-positive T lymphocytes, and the lesion involves the perineurium with marked edema. "Multifocal" is doing real work here: the attack picks out individual nerves and even individual fascicles, which is why the resulting weakness is patchy rather than following a plexus territory.
CD8-positive T lymphocyte CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive T lymphocyte, annotated with CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
inflammatory response in peripheral nerve GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response in peripheral nerve, annotated with inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
brachial plexus UBERON:0001814 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brachial plexus, annotated with brachial nerve plexus (UBERON:0001814). UBERON:0001814 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Severe Neuropathic Pain Attack
Focal Nerve Constriction and Torsion
Multifocal Axonal Injury
Show evidence (3 references)
PMID:8614534 SUPPORT Human Clinical
"There were florid multifocal mononuclear inflammatory cell infiltrates. Present evidence suggests that these brachial neuropathies have an immune basis."
Direct tissue evidence from brachial plexus biopsy in four patients, and the primary basis for the immune-mediated classification.
PMID:34054111 SUPPORT Human Clinical
"an auto-immune multifocal peripheral nervous system disorder that leaves many patients permanently impaired if not recognized and treated properly"
Characterises the disorder as autoimmune and multifocal, and notes the cost of missing it.
PMID:38248282 SUPPORT Human Clinical
"which involves the perineurium and is associated with marked edema, a mononuclear inflammatory infiltration, composed of CD8-positive T lymphocytes"
Identifies the effector cell population and the anatomical compartment of the lesion, which is what the cell-type and location bindings on this node record.
Severe Neuropathic Pain Attack
Mechanism confidence: Established
The illness opens with sudden, severe pain in the shoulder girdle. The pain is the presenting symptom and the window for immunomodulating treatment: it precedes the weakness, and it is while the patient is still in pain that corticosteroids are advised.
Downstream
Shoulder pain
Show evidence (1 reference)
PMID:32487526 SUPPORT Human Clinical
"is characterised by sudden pain attacks, followed by patchy muscle paresis in the upper extremity"
Establishes the defining temporal sequence of pain preceding patchy paresis, which the downstream edges of this entry encode.
Focal Nerve Constriction and Torsion
Mechanism confidence: Provisional
In a subset of patients the inflamed, swollen nerve develops a very focal constriction, with thickening proximal and distal to it, or frank torsion of the nerve or some of its fascicles. Ultrasound findings have been grouped as nerve swelling, swelling with incomplete constriction, swelling with complete constriction, and fascicular entwinement, which has been read as a continuum. The clinical importance is that these lesions do badly without surgery and well with it, so recognising them changes management.
Downstream
Multifocal Axonal Injury
Show evidence (2 references)
PMID:38248282 SUPPORT Human Clinical
"the hourglass constriction, which is characterized by a very focal constriction of a nerve, or part of it, usually associated with nerve thickening proximally and distally to the constriction"
Defines the structural lesion this node represents.
PMID:38248282 SUPPORT Human Clinical
"The prognosis of these conditions is often poor in the absence of any surgical treatment"
Supports treating the constriction as a mechanistically distinct, surgically addressable lesion rather than a radiological curiosity.
Multifocal Axonal Injury
Mechanism confidence: Established
The affected nerves sustain axonal loss, typically a severe axonotmesis on neurophysiological testing. This produces the patchy paresis and, over weeks, the amyotrophy the disease is named for. Importantly the axonal damage is not the whole story of long-term disability - see the maladaptive motor pattern node downstream.
Downstream
Upper limb muscle weakness
Skeletal muscle atrophy
Diaphragmatic weakness
Paresthesia
Reduced Nerve Endurance and Maladaptive Motor Pattern
Show evidence (1 reference)
PMID:38248282 SUPPORT Human Clinical
"usually a severe axonotmesis, documented during neurophysiological examination"
Characterises the nerve injury as severe axonotmesis on electrophysiology.
Reduced Nerve Endurance and Maladaptive Motor Pattern
Mechanism confidence: Established
The distinctive claim of the modern literature on this disease: persisting symptoms are caused mainly by a combination of decreased endurance in the affected nerves and an altered posture and movement pattern, and not by the axonal damage itself. This is why the long-term treatment target is scapular coordination and energy distribution rather than nerve regeneration, and why rehabilitation here is disease-modifying rather than supportive.
Downstream
Scapular winging
Fatigue
Show evidence (1 reference)
PMID:34054111 SUPPORT Human Clinical
"Long-term consequences are the rule, and persisting symptoms are mainly caused by a combination of decreased endurance in the affected nerves and an altered posture and movement pattern, not by the axonal damage itself."
States the claim directly, including the explicit negative - that axonal damage is not the main driver of persistent symptoms - which is the reason this node exists separately from the axonal injury node.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neuralgic Amyotrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Limbs 2
Upper limb muscle weakness VERY_FREQUENT HP:0003484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patchy upper limb paresis, annotated with Upper limb muscle weakness (HP:0003484). HP:0003484 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32487526 SUPPORT Human Clinical
"is characterised by sudden pain attacks, followed by patchy muscle paresis in the upper extremity"
Reports the patchy distribution of the weakness directly.
Scapular winging FREQUENT HP:0003691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scapular winging and dyskinesis, annotated with Scapular winging (HP:0003691). HP:0003691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26662794 SUPPORT INDIRECT Human Clinical
"a multidisciplinary rehabilitation approach focusing on scapular coordination, energy distribution strategies, and self-management is indicated"
Scapular coordination being the named rehabilitation target establishes scapular dysfunction as a core persisting problem. Indirect: the source prescribes the treatment rather than describing the sign.
Musculoskeletal 2
Skeletal muscle atrophy FREQUENT HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amyotrophy of the affected upper limb muscles, annotated with Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38248282 SUPPORT INDIRECT Human Clinical
"in its classic presentation is a brachial plexopathy or a multifocal neuropathy, involving mainly motor nerves of the upper limb with a monophasic course"
Supports the predominantly motor, upper-limb distribution that determines which muscles waste. Indirect for the atrophy itself, which the source names only in the disease term.
Diaphragmatic weakness OCCASIONAL HP:0009113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Phrenic neuropathy with diaphragmatic weakness, annotated with Diaphragmatic weakness (HP:0009113). HP:0009113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34054111 SUPPORT Human Clinical
"Phrenic nerve involvement occurs in 8% of all NA patients, often with debilitating consequences."
Gives both the frequency and the clinical weight of phrenic involvement.
Nervous System 1
Paresthesia FREQUENT HP:0003401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paresthesia in the affected nerve territory, annotated with Paresthesia (HP:0003401). HP:0003401 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38248282 SUPPORT Human Clinical
"sometimes preceded by paraesthesias in the territory of the involved nerve (in the case of a mixed nerve) and pain"
Documents paresthesia and its timing relative to the deficit. Note this sentence supports that paresthesia occurs and carries no frequency at all - the FREQUENT band comes from the cohort figure below, not from here.
PMID:16371410 SUPPORT Human Clinical
"Sensory involvement was quite common and found in 78.4% of patients but was clinically less impairing than the initial pain and subsequent paresis."
The frequency source. 78.4% falls in the FREQUENT band (30-79%). Note the denominator is the whole 246-patient series, which includes 47 hereditary cases alongside 199 idiopathic ones, so the figure is not purely of the acquired form this entry scopes to; the paper reports no separate sensory-involvement rate by subtype.
Constitutional 2
Shoulder pain VERY_FREQUENT HP:0030834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe shoulder-girdle pain, annotated with Shoulder pain (HP:0030834), qualified as temporality acute. HP:0030834 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:26662794 SUPPORT Human Clinical
"If patients are seen early and are still in pain, a short trial of high-dose oral corticosteroids is advised, and adequate analgesia may require opioids and non-steroidal anti-inflammatory drugs."
Establishes pain as the early clinical state that defines the treatment window and characterises its severity by the analgesia required.
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19254608 SUPPORT Human Clinical
"Over one third of the individual patients suffered from severe fatigue."
The frequency source, from 89 patients assessed on average two years after their last attack. Graded FREQUENT (30-79%) on "over one third" for severe fatigue; the same paper reports a quarter to a third with significant long-term fatigue on the looser criterion.
PMID:19254608 SUPPORT Human Clinical
"There was no correlation of pain or fatigue with the level of residual paresis on a Medical Research Council scale"
The reason this phenotype is wired to the endurance node rather than to axonal injury: fatigue tracks neither with how weak the patient is nor with psychological distress, which is the dissociation the endurance model predicts.
💊

Medical Actions

5
High-Dose Oral Corticosteroids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A short trial of high-dose oral corticosteroids in the acute phase, advised for patients seen early while still in pain. The aim is to damp the inflammatory attack during the window in which it is still active.
Mechanism Target:
Multifocal Inflammatory Attack on Peripheral Nerve — Suppresses the acute inflammatory attack on the nerve during the painful phase.
Show evidence (1 reference)
PMID:19321467 SUPPORT Human Clinical
"The median time until initial pain relief was lower in the study group (12.5 days vs 20.5 days), and a significantly higher percentage already recovered strength in the first month of treatment (18% vs 6.3%; p = 0.011)."
The comparative data behind the recommendation: 50 treated patients against a historical control group of 203 untreated ones. A retrospective case series with a historical control is weak for causal attribution, and the authors say so themselves - they recommend the regimen "pending a prospective, randomised trial verifying the results".
Show evidence (2 references)
PMID:26662794 SUPPORT Human Clinical
"If patients are seen early and are still in pain, a short trial of high-dose oral corticosteroids is advised"
States the recommendation and the timing constraint on it.
PMID:32487526 REFUTE Human Clinical
"treatment options were confined to application of corticosteroids and symptomatic management, without proven positive effects on long-term outcomes"
Refutes a long-term outcome benefit for corticosteroids. Recorded alongside the recommendation because the two claims are both true and about different endpoints: acute phase practice versus proven long-term effect.
Intravenous Immunoglobulin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Other
Immunomodulating treatment in the acute phase, cited alongside steroids as potentially beneficial. Early immunomodulation is presented as important for optimal recovery.
Mechanism Target:
Multifocal Inflammatory Attack on Peripheral Nerve — Immunomodulation directed at the acute immune attack on the nerve.
Show evidence (1 reference)
PMID:34054111 SUPPORT Human Clinical
"Acute phase treatment of NA with steroids or i.v. immunoglobulin may benefit patients."
Names IVIG as an acute-phase option. The hedged "may benefit" is the strength of the claim and is not upgraded here.
Peripheral Nerve Surgery
Action: Peripheral nerve surgery for hourglass constrictionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Peripheral nerve surgery for hourglass constriction, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical treatment of hourglass constrictions and nerve torsion identified on high-resolution imaging. This is the treatment that the structural findings made possible, and it applies to the constriction subgroup rather than to neuralgic amyotrophy generally.
Mechanism Target:
Focal Nerve Constriction and Torsion — Addresses the focal structural lesion directly, by neurolysis, resection or grafting of the constricted segment.
Show evidence (3 references)
PMID:32487526 SUPPORT Human Clinical
"surgery has shown to improve clinical outcomes in such cases, indicating the viability of peripheral nerve surgery as a valuable treatment option in NA"
Supports surgery for the imaging-identified constriction subgroup specifically.
PMID:38248282 SUPPORT Human Clinical
"The prognosis is generally favorable after surgery, with a high rate of good motor recovery."
Independent statement of post-surgical outcome in the constriction subgroup.
PMID:32868098 SUPPORT Human Clinical
"Nine of 11 operative patients experienced clinical recovery compared with 3 of 13 nonsurgical patients."
The comparative outcome behind the recommendation, quoted as counts rather than as a percentage because the arms are 11 and 13 patients. The paper grades itself Therapeutic IV, and allocation was not randomised, so this establishes an association between surgery and recovery in a selected group, not an effect size.
Phrenic Nerve Reconstruction
Action: Phrenic nerve reconstructionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Phrenic nerve reconstruction, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical repair of the injured phrenic nerve for symptomatic diaphragm paralysis, in selected patients. Curated because diaphragmatic weakness is a phenotype of this entry with no other treatment linked to it, and because it is the intervention that follows from the HEV-associated phrenic presentation. The evidence is weaker than for the other surgical entry here: this is a narrative review of phrenic nerve reconstruction across all causes of phrenic injury, of which neuralgic amyotrophy is one, not a series of NA patients. It reports no NA-specific outcome.
Mechanism Target:
Diaphragmatic weakness — Restores functional diaphragmatic activity by repairing the nerve lesion, rather than compensating for it mechanically as diaphragm plication does.
Show evidence (2 references)
PMID:36031309 SUPPORT Human Clinical
"Common etiologies of phrenic injuries include cervical trauma, iatrogenic injury in the neck or chest, and neuralgic amyotrophy."
Establishes that neuralgic amyotrophy is among the phrenic injuries this operation is performed for, which is what makes the treatment in scope for this entry.
PMID:36031309 SUPPORT Human Clinical
"Surgical repair of the nerve injury to restore functional diaphragmatic activity, termed phrenic nerve reconstruction, is a safe and effective alternative to static repositioning of the diaphragm (diaphragm plication), in properly selected patients."
The efficacy claim, with the authors' own restriction to "properly selected patients" preserved. A review statement, not a trial result.
Scapular Coordination Rehabilitation
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Platform: Behavioral / lifestyle
Multidisciplinary rehabilitation focused on scapular coordination, energy distribution strategies and self-management. Because persisting symptoms are attributed to reduced nerve endurance and an altered movement pattern rather than to axon loss, this targets the actual driver of long-term disability and is not merely supportive.
Mechanism Target:
Reduced Nerve Endurance and Maladaptive Motor Pattern — Retrains scapular coordination and paces energy expenditure, addressing the movement pattern and endurance limitation that carry the persisting symptoms.
Show evidence (5 references)
PMID:26662794 SUPPORT Human Clinical
"Persistent complaints are common, and a multidisciplinary rehabilitation approach focusing on scapular coordination, energy distribution strategies, and self-management is indicated."
States the indication and the specific content of the rehabilitation programme.
PMID:34054111 SUPPORT Human Clinical
"Patients benefit from specific rehabilitation treatment."
Independent statement of benefit from targeted rehabilitation.
PMID:36697215 SUPPORT Human Clinical
"The mean group difference adjusted for sex, age and SRQ-DLV baseline score was 8.60 (95%CI: 0.26 to 16.94, p=0.044)."
The primary outcome of the only randomised trial of this intervention, and the strongest interventional evidence in this disease. Note the confidence interval nearly touches zero and the trial randomised 47 patients but analysed 37 after dropout, so the effect is real but imprecise.
+ 2 more references
🌍

Environmental Factors

2
Antecedent infection or vaccination
antecedent infection or vaccination ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is antecedent infection or vaccination, annotated with exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
The general immune trigger the first pathophysiology node depends on. A prospective matched case-control study confirmed a microbiologically documented infectious trigger in 26.3% of patients and considered COVID-19 vaccination a potential trigger in a further 12.3%, giving a confirmed immune trigger in 38.6% overall. An acute viral infection was associated with bilateral brachial plexus involvement, which is the clinically useful part: the trigger is not just antecedent, it shapes the attack. This is the better-evidenced and more general trigger claim; the hepatitis E entry below is a specific, clinically distinctive instance of it rather than an alternative to it. Note that a confirmed trigger in 38.6% means the majority of attacks still have none identified, so this is a contributing precipitant in a susceptible individual and not a necessary cause.
Show evidence (3 references)
PMID:39364568 SUPPORT Human Clinical
"NA onset was preceded by a symptomatic infectious trigger confirmed by microbiological tests in 15/57 (26.3%) patients."
The infection component, confirmed microbiologically rather than by history. Each case was matched to a healthy control for age, sex, residence and blood collection time, which is what distinguishes this from the uncontrolled series elsewhere in this entry.
PMID:39364568 SUPPORT Human Clinical
"An acute viral infection was associated with a bilateral involvement of the brachial plexus (p = 0.003, Cramèr's V = 0.43)."
The trigger is associated with the anatomical pattern of the attack, not only with its occurrence. Quoted with the paper's own spelling of the statistic's name.
PMID:39364568 SUPPORT Human Clinical
"Coronavirus disease 2019 vaccination was considered a potential trigger in 7/57 (12.3%) subjects."
The vaccination component. The authors write "considered a potential trigger", which is weaker than the microbiologically confirmed infections above, and the wording is kept.
Mechanism Target:
TRIGGERS Multifocal Inflammatory Attack on Peripheral Nerve — An antecedent immune challenge precipitates the multifocal inflammatory attack in a susceptible plexus.
Show evidence (1 reference)
PMID:39364568 SUPPORT Human Clinical
"Confirmed immune triggers (infection or vaccination) preceded disease onset in 22/57 (38.6%) NA cases."
The headline figure from the only matched case-control study of triggers in this disease, with serology performed centrally rather than relying on patient report.
Hepatitis E virus infection
exposure to hepatitis E virus ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to hepatitis E virus, annotated with exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
exposure_term is bound to the broader ECTO:3000001 (exposure to virus) with the specificity carried in preferred_term. ECTO has no hepatitis exposure term: searching t~hepat returns only ECTO:9001877 (hepatotoxic agent) and ECTO:9001927 (hepatoprotective agent), and t~virus returns only ECTO:3000001, ECTO:2000053 (HPV) and ECTO:3000002 (Enterovirus). This is a confirmed absence, established on a working adapter by the reviewer of PR #10998 after my own local ECTO index returned nothing even for a control query. Recorded as an absence rather than as an unanswered question, because the two are different claims.
HEV, characteristically genotype 3, is a recurrently reported trigger of a neuralgic amyotrophy attack, and the association is clinically distinctive rather than incidental: the HEV-associated cases are enriched for phrenic nerve involvement and diaphragmatic paralysis rather than the usual shoulder-girdle picture. One series found 13 such patients in three years with normal liver enzymes in all of them, which is why the association is missed - the trigger leaves no hepatic signal by the time the neuropathy presents. Curated as an environmental trigger rather than a cause. NA is not a manifestation of hepatitis E; the virus is one of several precipitants acting on an already-susceptible plexus, which is the model this entry's first pathophysiology node describes.
Show evidence (2 references)
PMID:38657646 SUPPORT Human Clinical
"In all cases, O2C hepatitis genotype 3 was identified."
Identifies the genotype across the whole series, which is what makes this a specific exposure rather than "a viral illness".
PMID:38657646 SUPPORT Human Clinical
"Liver values were normal in all patients."
The reason the trigger is missed. By the time the neuropathy presents there is no hepatic signal to prompt HEV serology, so the exposure is only found when it is looked for.
Mechanism Target:
TRIGGERS Multifocal Inflammatory Attack on Peripheral Nerve — Infection precipitates the immune attack on the plexus, with a predilection for the phrenic nerve that distinguishes HEV-triggered attacks from other precipitants.
Show evidence (2 references)
PMID:38657646 SUPPORT Human Clinical
"NA that shows involvement of the phrenic nerve resulting in diaphragmatic dysfunction and dyspnoea, may be associated with HEV infection"
States the association and the phrenic predilection that makes it recognisable. Note the authors' own hedge - "may be associated" - which is why this edge is a trigger rather than a cause.
PMID:40534221 SUPPORT Human Clinical
"The diagnosis of neuralgic amyotrophy with diaphragmatic paralysis secondary to HEV was made"
A single worked case with serology, viral load and electrodiagnostic confirmation of phrenic involvement.
🔬

Diagnosis

2
Clinical diagnosis with exclusion of alternative causes
Neuralgic amyotrophy is diagnosed clinically. Ancillary studies are used to exclude infectious or malignant causes or to assess a differential diagnosis, rather than to confirm the disease. High-resolution ultrasound and MRI have a distinct role: identifying hourglass constrictions or nerve torsion pre-surgically, which changes management for that subgroup.
Show evidence (4 references)
PMID:26662794 SUPPORT Human Clinical
"NA is a clinical diagnosis, and ancillary studies serve to exclude infectious or malignant causes or to assess a differential diagnosis."
States the diagnostic model and the limited role of ancillary testing.
PMID:38248282 SUPPORT Human Clinical
"It is now widely accepted that nerve imaging is necessary in identifying hourglass constrictions/nerve torsion pre-surgically in patients with an acute mononeuropathy/plexopathy."
Establishes the specific, surgical role of nerve imaging.
PMID:36214185 SUPPORT Human Clinical
"US and MRN showed nerve abnormalities within 1 mo from NA onset in 90% of patients."
Puts a number on the imaging claim above. 39 patients imaged within 31 days of onset, so this is the yield in the acute window specifically, not in a chronic presentation.
+ 1 more reference
Hepatitis E serology in phrenic or diaphragmatic involvement
Test for HEV IgM and IgG with serum HEV RNA when the phrenic nerve or diaphragm is involved. This is the action that follows from the observation curated in the environmental section: the reason HEV-associated cases are missed is that liver enzymes are normal by the time the neuropathy presents, so nothing prompts the serology unless it is asked for on the neurological picture alone. The recommendation is stated at a lower level of confidence than the imaging above. It rests on two small uncontrolled series, plus the case-control study's suggestion to test acute-phase patients where there is bilateral involvement or hepatitis. No study has evaluated this as a diagnostic strategy, so its yield is unknown.
Show evidence (2 references)
PMID:38657646 SUPPORT Human Clinical
"Therefore, even in diaphragmatic dysfunction without NA symptoms and causative damaging event, HEV infection should be considered, as it may represent a subform of NA with only phrenic nerve involvement."
The authors' own recommendation, extending past NA into unexplained diaphragmatic dysfunction. Quoted with the hedges ("should be considered", "may represent") intact.
PMID:39364568 SUPPORT Human Clinical
"We suggest to test NA patients in the acute phase for intracellular antigens, especially in the case of concomitant bilateral involvement and hepatitis."
Independent support for testing in the acute phase, from the case-control study, with the trigger pattern that should raise suspicion.
📈

Progression

3
Acute pain phase
Age: First ~4 weeks from onset
Abrupt onset of severe continuous neuropathic pain in the shoulder and upper arm, lasting around four weeks on average. This phase is the therapeutic window for corticosteroids.
Show evidence (1 reference)
PMID:16371410 SUPPORT Human Clinical
"Generally, the course of the pain manifests itself in three consecutive phases with an initial severe, continuous pain lasting for approximately 4 weeks on average."
Establishes both the three-phase structure and the duration of the first phase, in the largest series of this disease.
Paresis phase
As the initial pain subsides, patchy flaccid paresis and amyotrophy appear in the affected nerve distributions, most often upper and middle trunk.
Show evidence (1 reference)
PMID:16371410 SUPPORT Human Clinical
"We investigated the symptoms, course and prognosis of neuralgic amyotrophy (NA) in a large group of patients with idiopathic neuralgic amyotrophy (INA, n = 199) and hereditary neuralgic amyotrophy (HNA, n = 47) to gain more insight into the broad clinical spectrum of the disorder. ... Generally,..."
Identifies neuralgic amyotrophy, initial pain followed by paresis and the common patchy upper/middle-trunk nerve distribution.
Residual phase
Slow and often incomplete recovery. This is the phase the modern rehabilitation approach targets, and the phase whose burden the older literature understated.
Show evidence (1 reference)
PMID:16371410 SUPPORT Human Clinical
"Overall recovery was less favourable than usually assumed, with persisting pain and paresis in approximately two-thirds of the patients who were followed for 3 years or more."
The prognosis correction that underpins this entry's treatment section. Two-thirds with persisting symptoms at three years is the reason rehabilitation is curated as disease-modifying rather than supportive.
📊

Prevalence

1
Worldwide
Annual Incidence 100.0 per 100,000 >1 in 1,000 per year
Reported as an incidence of 1 per 1,000 individuals, roughly an order of magnitude above the figure carried in the older literature. Converted as 1/1,000 = 100 per 100,000.
Show evidence (1 reference)
PMID:26662794 SUPPORT Human Clinical
"It is not rare, with an incidence of 1 per 1,000 individuals, but it is still often missed."
The source of the incidence figure and of the underdiagnosis claim.
{ }

Source YAML

click to show 
name: Neuralgic Amyotrophy
category: Complex
creation_date: "2026-09-04T00:00:00Z"
synonyms:
- Parsonage-Turner syndrome
- brachial plexus neuritis
- acute brachial plexus neuritis
- immune brachial plexus neuropathy
- neuralgic shoulder amyotrophy
description: >-
  Neuralgic amyotrophy is an immune-mediated multifocal peripheral neuropathy that begins with
  an abrupt attack of severe shoulder-girdle pain and is followed, as the pain subsides, by
  patchy weakness and wasting in the upper limb. It is a clinical diagnosis; ancillary testing
  serves mainly to exclude infectious or malignant causes.

  This entry covers the acquired, idiopathic form. Hereditary neuralgic amyotrophy, caused by
  SEPTIN9 duplication, is a separate MONDO concept with a different initiating lesion and is
  deliberately not folded in here.

  Three things about this disease are commonly got wrong, and the entry is organised around
  them.

  It is not rare. Incidence is about 1 per 1,000 individuals, an order of magnitude above the
  figure the older literature carried, and it is still frequently missed.

  It is not benign. The original descriptions emphasised spontaneous good recovery, but the
  majority of patients never achieve full recovery, and long-term consequences are the rule
  rather than the exception.

  Most importantly, the residual disability is not simply the axonal damage. Persisting symptoms
  are attributed mainly to reduced endurance in the affected nerves combined with an altered
  posture and movement pattern - not to the axon loss itself. That distinction is what makes
  scapular-coordination rehabilitation a mechanistically targeted treatment rather than generic
  supportive care, and it is why the entry carries a separate maladaptive-motor-pattern arm
  downstream of the nerve injury.

  The other development worth recording is structural. High-resolution ultrasound and MRI
  identified hourglass-like constrictions - focal narrowings with proximal and distal nerve
  thickening, involving the perineurium, with marked edema and a mononuclear infiltrate of
  CD8-positive T lymphocytes. Whether these are a distinct entity or a late stage of the same
  inflammatory process is genuinely unsettled, and is recorded as a controversy rather than
  resolved in the causal chain.
notes: >-
  A note on this entry's evidence base, because it is not visible from the evidence items
  themselves. Sixteen references: five are narrative reviews (PMID:26662794, PMID:32487526,
  PMID:34054111, PMID:38248282, PMID:39402917) carrying MEDLINE publication type "Review" with
  no primary patient data of their own, and one (PMID:36031309) is a review of phrenic nerve
  reconstruction across all causes rather than in this disease. The remaining ten report
  original human observations, and they carry the load for the entry's quantitative claims:

  - PMID:36697215 - randomised controlled trial (n=47 randomised, 37 analysed) of the
    rehabilitation programme, the only randomised evidence in this disease.
  - PMID:16371410 - 246-patient clinical series, the source of the three-phase course, the
    sensory-involvement frequency and the two-thirds persisting-symptom prognosis. Note this
    cohort mixes 199 idiopathic with 47 hereditary cases, while this entry scopes to the
    acquired form.
  - PMID:39364568 - prospective matched case-control (n=57) of immune triggers, with central
    serology.
  - PMID:19254608 - 89 patients assessed on average two years out, for long-term fatigue.
  - PMID:36214185 - 39 patients imaged within 31 days, for the imaging yields.
  - PMID:19321467 - 50 treated patients against a historical control group of 203, for the
    corticosteroid effect. Retrospective with a historical control, which the authors flag.
  - PMID:32868098 - 24 patients, non-randomised, for the surgical comparison. Graded
    Therapeutic IV by its own authors.
  - PMID:8614534 - the four-patient brachial plexus biopsy series, still the only direct tissue
    evidence for the immune-mediated mechanism this entry is built on.
  - PMID:38657646 (13 patients) and PMID:40534221 (2 patients) - the hepatitis E association,
    both uncontrolled.

  Every one of these is graded HUMAN_CLINICAL, which is what the schema's definition supports
  and the dominant convention in this knowledge base. But an RCT, a 246-patient series, a
  four-patient biopsy series and a two-patient case report all carry that identical value, and a
  reader cannot tell them apart at the evidence item. That is why the distinctions above are
  written out here. See dismech#9421 and dismech#9827.

  A comparative-species model was considered and rejected. The deep-research report for this
  disease offers feline hypertrophic brachial plexus neuritis (PMID:29925717) as a naturally
  occurring analogue. Reading the source rather than the summary, that cat had a chronic
  hypertrophic demyelinating neuritis with onion-bulb formation, which its own authors compare
  to human CIDP rather than to neuralgic amyotrophy. NA is an acute, painful, multifocal axonal
  process. The shared feature is brachial plexus inflammation, which is not enough to make it a
  model of this disease, so it is deliberately not curated as one.

disease_term:
  preferred_term: neuralgic amyotrophy
  term:
    id: MONDO:0017362
    label: neuralgic amyotrophy
parents:
- Acquired Peripheral Neuropathy
references:
- reference: PMID:26662794
  title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
- reference: PMID:34054111
  title: "Neuralgic amyotrophy."
- reference: PMID:32487526
  title: "Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment."
- reference: PMID:38248282
  title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
- reference: PMID:8614534
  title: "Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis."
- reference: PMID:38657646
  title: "Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature."
- reference: PMID:40534221
  title: "Neurological Manifestations of HEV Infection: A Rare Phenomenon or an Underrecognized Reality?"
- reference: PMID:16371410
  title: "The clinical spectrum of neuralgic amyotrophy in 246 cases."
- reference: PMID:19254608
  title: "Long-term pain, fatigue, and impairment in neuralgic amyotrophy."
- reference: PMID:36697215
  title: "Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial."
- reference: PMID:39402917
  title: "Neuralgic amyotrophy: An update in evaluation, diagnosis, and treatment approaches."
- reference: PMID:39364568
  title: Immune triggers preceding neuralgic amyotrophy.
- reference: PMID:19321467
  title: "Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study."
- reference: PMID:36214185
  title: Imaging of neuralgic amyotrophy in the acute phase.
- reference: PMID:32868098
  title: "Outcomes of Microneurolysis of Hourglass Constrictions in Chronic Neuralgic Amyotrophy."
- reference: PMID:36031309
  title: Phrenic nerve paralysis and phrenic nerve reconstruction surgery.
pathophysiology:
- name: Multifactorial Susceptibility to Brachial Plexus Immune Attack
  description: >-
    Neuralgic amyotrophy is not attributed to a single initiating lesion. Genetic, biomechanical
    and immunologic factors are all implicated, and it is this multifactorial etiology - rather
    than a lack of study - that limits the ability to predict or prevent the recurrences that
    are common in this disease. The biomechanical component is what is thought to localise an
    otherwise systemic immune event to particular nerves.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Multifocal Inflammatory Attack on Peripheral Nerve
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrences are common, yet the proposed multifactorial etiology, which includes genetic, biomechanical, and immunologic factors, limits our capacity to predict or prevent them."
    explanation: >-
      States the three-component etiologic model and its practical consequence, which is why
      this node is marked provisional rather than established.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune, genetic, infectious and mechanical processes are thought to be involved, but etiopathogenesis is still incompletely understood"
    explanation: >-
      An independent review reaching the same multifactorial conclusion and stating explicitly
      that the etiopathogenesis is not settled.
- name: Multifocal Inflammatory Attack on Peripheral Nerve
  description: >-
    Brachial plexus biopsy in affected patients shows florid multifocal mononuclear inflammatory
    cell infiltrates, which is the direct histopathological basis for calling the disorder
    immune-mediated. The infiltrate in the constricted segments is composed of CD8-positive T
    lymphocytes, and the lesion involves the perineurium with marked edema. "Multifocal" is
    doing real work here: the attack picks out individual nerves and even individual fascicles,
    which is why the resulting weakness is patchy rather than following a plexus territory.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: CD8-positive T lymphocyte
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: inflammatory response in peripheral nerve
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  locations:
  - preferred_term: brachial plexus
    term:
      id: UBERON:0001814
      label: brachial nerve plexus
  downstream:
  - target: Severe Neuropathic Pain Attack
    causal_link_type: DIRECT
  - target: Focal Nerve Constriction and Torsion
    causal_link_type: DIRECT
  - target: Multifocal Axonal Injury
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:8614534
    reference_title: "Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were florid multifocal mononuclear inflammatory cell infiltrates. Present evidence suggests that these brachial neuropathies have an immune basis."
    explanation: >-
      Direct tissue evidence from brachial plexus biopsy in four patients, and the primary basis
      for the immune-mediated classification.
  - reference: PMID:34054111
    reference_title: "Neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an auto-immune multifocal peripheral nervous system disorder that leaves many patients permanently impaired if not recognized and treated properly"
    explanation: Characterises the disorder as autoimmune and multifocal, and notes the cost of missing it.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which involves the perineurium and is associated with marked edema, a mononuclear inflammatory infiltration, composed of CD8-positive T lymphocytes"
    explanation: >-
      Identifies the effector cell population and the anatomical compartment of the lesion,
      which is what the cell-type and location bindings on this node record.
- name: Severe Neuropathic Pain Attack
  description: >-
    The illness opens with sudden, severe pain in the shoulder girdle. The pain is the
    presenting symptom and the window for immunomodulating treatment: it precedes the weakness,
    and it is while the patient is still in pain that corticosteroids are advised.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Shoulder pain
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32487526
    reference_title: "Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterised by sudden pain attacks, followed by patchy muscle paresis in the upper extremity"
    explanation: >-
      Establishes the defining temporal sequence of pain preceding patchy paresis, which the
      downstream edges of this entry encode.
- name: Focal Nerve Constriction and Torsion
  description: >-
    In a subset of patients the inflamed, swollen nerve develops a very focal constriction, with
    thickening proximal and distal to it, or frank torsion of the nerve or some of its fascicles.
    Ultrasound findings have been grouped as nerve swelling, swelling with incomplete
    constriction, swelling with complete constriction, and fascicular entwinement, which has
    been read as a continuum. The clinical importance is that these lesions do badly without
    surgery and well with it, so recognising them changes management.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Multifocal Axonal Injury
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the hourglass constriction, which is characterized by a very focal constriction of a nerve, or part of it, usually associated with nerve thickening proximally and distally to the constriction"
    explanation: Defines the structural lesion this node represents.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prognosis of these conditions is often poor in the absence of any surgical treatment"
    explanation: >-
      Supports treating the constriction as a mechanistically distinct, surgically addressable
      lesion rather than a radiological curiosity.
- name: Multifocal Axonal Injury
  description: >-
    The affected nerves sustain axonal loss, typically a severe axonotmesis on
    neurophysiological testing. This produces the patchy paresis and, over weeks, the amyotrophy
    the disease is named for. Importantly the axonal damage is not the whole story of long-term
    disability - see the maladaptive motor pattern node downstream.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Upper limb muscle weakness
    causal_link_type: DIRECT
  - target: Skeletal muscle atrophy
    causal_link_type: DIRECT
  - target: Diaphragmatic weakness
    causal_link_type: DIRECT
  - target: Paresthesia
    causal_link_type: DIRECT
  - target: Reduced Nerve Endurance and Maladaptive Motor Pattern
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "usually a severe axonotmesis, documented during neurophysiological examination"
    explanation: Characterises the nerve injury as severe axonotmesis on electrophysiology.
- name: Reduced Nerve Endurance and Maladaptive Motor Pattern
  description: >-
    The distinctive claim of the modern literature on this disease: persisting symptoms are
    caused mainly by a combination of decreased endurance in the affected nerves and an altered
    posture and movement pattern, and not by the axonal damage itself. This is why the
    long-term treatment target is scapular coordination and energy distribution rather than
    nerve regeneration, and why rehabilitation here is disease-modifying rather than supportive.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Scapular winging
    causal_link_type: DIRECT
  - target: Fatigue
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34054111
    reference_title: "Neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term consequences are the rule, and persisting symptoms are mainly caused by a combination of decreased endurance in the affected nerves and an altered posture and movement pattern, not by the axonal damage itself."
    explanation: >-
      States the claim directly, including the explicit negative - that axonal damage is not the
      main driver of persistent symptoms - which is the reason this node exists separately from
      the axonal injury node.
phenotypes:
- category: Neurologic
  name: Shoulder pain
  description: >-
    Sudden, severe pain in the shoulder girdle opening the illness, before any weakness is
    apparent. Adequate analgesia may require opioids as well as NSAIDs.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Severe shoulder-girdle pain
    term:
      id: HP:0030834
      label: Shoulder pain
    temporality: ACUTE
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If patients are seen early and are still in pain, a short trial of high-dose oral corticosteroids is advised, and adequate analgesia may require opioids and non-steroidal anti-inflammatory drugs."
    explanation: >-
      Establishes pain as the early clinical state that defines the treatment window and
      characterises its severity by the analgesia required.
- category: Neurologic
  name: Upper limb muscle weakness
  description: >-
    Patchy paresis of the upper extremity following the pain. The patchiness reflects the
    multifocal nature of the nerve attack rather than a single plexus lesion.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Patchy upper limb paresis
    term:
      id: HP:0003484
      label: Upper limb muscle weakness
  evidence:
  - reference: PMID:32487526
    reference_title: "Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterised by sudden pain attacks, followed by patchy muscle paresis in the upper extremity"
    explanation: Reports the patchy distribution of the weakness directly.
- category: Neurologic
  name: Skeletal muscle atrophy
  description: >-
    Wasting of the denervated shoulder-girdle and upper limb muscles, the amyotrophy in the
    disease name, developing over weeks after the axonal injury.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Amyotrophy of the affected upper limb muscles
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in its classic presentation is a brachial plexopathy or a multifocal neuropathy, involving mainly motor nerves of the upper limb with a monophasic course"
    explanation: >-
      Supports the predominantly motor, upper-limb distribution that determines which muscles
      waste. Indirect for the atrophy itself, which the source names only in the disease term.
    directness: INDIRECT
- category: Neurologic
  name: Scapular winging
  description: >-
    Abnormal scapular position and movement, both from weakness of the periscapular muscles and
    from the altered movement pattern that develops afterwards. It is the specific target of
    the rehabilitation strategy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scapular winging and dyskinesis
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a multidisciplinary rehabilitation approach focusing on scapular coordination, energy distribution strategies, and self-management is indicated"
    explanation: >-
      Scapular coordination being the named rehabilitation target establishes scapular
      dysfunction as a core persisting problem. Indirect: the source prescribes the treatment
      rather than describing the sign.
    directness: INDIRECT
- category: Respiratory
  name: Diaphragmatic weakness
  description: >-
    Phrenic nerve involvement occurs in 8% of patients and is often debilitating. It is called
    out separately in the literature because identifying it early matters for recovery.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Phrenic neuropathy with diaphragmatic weakness
    term:
      id: HP:0009113
      label: Diaphragmatic weakness
  evidence:
  - reference: PMID:34054111
    reference_title: "Neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Phrenic nerve involvement occurs in 8% of all NA patients, often with debilitating consequences."
    explanation: Gives both the frequency and the clinical weight of phrenic involvement.
- category: Neurologic
  name: Paresthesia
  description: >-
    Sensory symptoms in the territory of an affected mixed nerve, sometimes preceding the motor
    deficit. The disease is predominantly but not exclusively motor.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Paresthesia in the affected nerve territory
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sometimes preceded by paraesthesias in the territory of the involved nerve (in the case of a mixed nerve) and pain"
    explanation: >-
      Documents paresthesia and its timing relative to the deficit. Note this sentence supports
      that paresthesia occurs and carries no frequency at all - the FREQUENT band comes from the
      cohort figure below, not from here.
  - reference: PMID:16371410
    reference_title: "The clinical spectrum of neuralgic amyotrophy in 246 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensory involvement was quite common and found in 78.4% of patients but was clinically less impairing than the initial pain and subsequent paresis."
    explanation: >-
      The frequency source. 78.4% falls in the FREQUENT band (30-79%). Note the denominator is
      the whole 246-patient series, which includes 47 hereditary cases alongside 199 idiopathic
      ones, so the figure is not purely of the acquired form this entry scopes to; the paper
      reports no separate sensory-involvement rate by subtype.
- category: Neurologic
  name: Fatigue
  description: >-
    Persistent fatigue is one of the two dominant residual symptoms, alongside pain, and is the
    clinical readout of this entry's central mechanistic claim: it is not explained by residual
    paresis. The cohort study found no correlation between fatigue and the level of residual
    weakness on the MRC scale, which is the observation that separates this from simple
    deconditioning after nerve injury, and which is why the long-term treatment target is
    energy distribution rather than strength.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:19254608
    reference_title: "Long-term pain, fatigue, and impairment in neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over one third of the individual patients suffered from severe fatigue."
    explanation: >-
      The frequency source, from 89 patients assessed on average two years after their last
      attack. Graded FREQUENT (30-79%) on "over one third" for severe fatigue; the same paper
      reports a quarter to a third with significant long-term fatigue on the looser criterion.
  - reference: PMID:19254608
    reference_title: "Long-term pain, fatigue, and impairment in neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no correlation of pain or fatigue with the level of residual paresis on a Medical Research Council scale"
    explanation: >-
      The reason this phenotype is wired to the endurance node rather than to axonal injury:
      fatigue tracks neither with how weak the patient is nor with psychological distress, which
      is the dissociation the endurance model predicts.
environmental:
- name: Antecedent infection or vaccination
  description: >-
    The general immune trigger the first pathophysiology node depends on. A prospective matched
    case-control study confirmed a microbiologically documented infectious trigger in 26.3% of
    patients and considered COVID-19 vaccination a potential trigger in a further 12.3%, giving
    a confirmed immune trigger in 38.6% overall. An acute viral infection was associated with
    bilateral brachial plexus involvement, which is the clinically useful part: the trigger is
    not just antecedent, it shapes the attack.

    This is the better-evidenced and more general trigger claim; the hepatitis E entry below is
    a specific, clinically distinctive instance of it rather than an alternative to it. Note
    that a confirmed trigger in 38.6% means the majority of attacks still have none identified,
    so this is a contributing precipitant in a susceptible individual and not a necessary cause.
  exposure_term:
    preferred_term: antecedent infection or vaccination
    term:
      id: ECTO:3000001
      label: exposure to virus
  influences_mechanisms:
  - target: Multifocal Inflammatory Attack on Peripheral Nerve
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      An antecedent immune challenge precipitates the multifocal inflammatory attack in a
      susceptible plexus.
    evidence:
    - reference: PMID:39364568
      reference_title: Immune triggers preceding neuralgic amyotrophy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Confirmed immune triggers (infection or vaccination) preceded disease onset in 22/57 (38.6%) NA cases."
      explanation: >-
        The headline figure from the only matched case-control study of triggers in this
        disease, with serology performed centrally rather than relying on patient report.
  evidence:
  - reference: PMID:39364568
    reference_title: Immune triggers preceding neuralgic amyotrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NA onset was preceded by a symptomatic infectious trigger confirmed by microbiological tests in 15/57 (26.3%) patients."
    explanation: >-
      The infection component, confirmed microbiologically rather than by history. Each case was
      matched to a healthy control for age, sex, residence and blood collection time, which is
      what distinguishes this from the uncontrolled series elsewhere in this entry.
  - reference: PMID:39364568
    reference_title: Immune triggers preceding neuralgic amyotrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An acute viral infection was associated with a bilateral involvement of the brachial plexus (p = 0.003, Cram\u00e8r's V = 0.43)."
    explanation: >-
      The trigger is associated with the anatomical pattern of the attack, not only with its
      occurrence. Quoted with the paper's own spelling of the statistic's name.
  - reference: PMID:39364568
    reference_title: Immune triggers preceding neuralgic amyotrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronavirus disease 2019 vaccination was considered a potential trigger in 7/57 (12.3%) subjects."
    explanation: >-
      The vaccination component. The authors write "considered a potential trigger", which is
      weaker than the microbiologically confirmed infections above, and the wording is kept.
- name: Hepatitis E virus infection
  description: >-
    HEV, characteristically genotype 3, is a recurrently reported trigger of a neuralgic
    amyotrophy attack, and the association is clinically distinctive rather than incidental: the
    HEV-associated cases are enriched for phrenic nerve involvement and diaphragmatic paralysis
    rather than the usual shoulder-girdle picture. One series found 13 such patients in three
    years with normal liver enzymes in all of them, which is why the association is missed - the
    trigger leaves no hepatic signal by the time the neuropathy presents.

    Curated as an environmental trigger rather than a cause. NA is not a manifestation of
    hepatitis E; the virus is one of several precipitants acting on an already-susceptible
    plexus, which is the model this entry's first pathophysiology node describes.
  exposure_term:
    preferred_term: exposure to hepatitis E virus
    term:
      id: ECTO:3000001
      label: exposure to virus
  influences_mechanisms:
  - target: Multifocal Inflammatory Attack on Peripheral Nerve
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Infection precipitates the immune attack on the plexus, with a predilection for the
      phrenic nerve that distinguishes HEV-triggered attacks from other precipitants.
    evidence:
    - reference: PMID:38657646
      reference_title: "Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NA that shows involvement of the phrenic nerve resulting in diaphragmatic dysfunction and dyspnoea, may be associated with HEV infection"
      explanation: >-
        States the association and the phrenic predilection that makes it recognisable. Note the
        authors' own hedge - "may be associated" - which is why this edge is a trigger rather
        than a cause.
    - reference: PMID:40534221
      reference_title: "Neurological Manifestations of HEV Infection: A Rare Phenomenon or an Underrecognized Reality?"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The diagnosis of neuralgic amyotrophy with diaphragmatic paralysis secondary to HEV was made"
      explanation: A single worked case with serology, viral load and electrodiagnostic confirmation of phrenic involvement.
  evidence:
  - reference: PMID:38657646
    reference_title: "Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all cases, O2C hepatitis genotype 3 was identified."
    explanation: Identifies the genotype across the whole series, which is what makes this a specific exposure rather than "a viral illness".
  - reference: PMID:38657646
    reference_title: "Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver values were normal in all patients."
    explanation: >-
      The reason the trigger is missed. By the time the neuropathy presents there is no hepatic
      signal to prompt HEV serology, so the exposure is only found when it is looked for.
  notes: >-
    exposure_term is bound to the broader ECTO:3000001 (exposure to virus) with the specificity
    carried in preferred_term. ECTO has no hepatitis exposure term: searching t~hepat returns
    only ECTO:9001877 (hepatotoxic agent) and ECTO:9001927 (hepatoprotective agent), and t~virus
    returns only ECTO:3000001, ECTO:2000053 (HPV) and ECTO:3000002 (Enterovirus). This is a
    confirmed absence, established on a working adapter by the reviewer of PR #10998 after my
    own local ECTO index returned nothing even for a control query. Recorded as an absence
    rather than as an unanswered question, because the two are different claims.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 100.0
  notes: >-
    Reported as an incidence of 1 per 1,000 individuals, roughly an order of magnitude above
    the figure carried in the older literature. Converted as 1/1,000 = 100 per 100,000.
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is not rare, with an incidence of 1 per 1,000 individuals, but it is still often missed."
    explanation: The source of the incidence figure and of the underdiagnosis claim.
progression:
- phase: Acute pain phase
  age_range: First ~4 weeks from onset
  notes: >-
    Abrupt onset of severe continuous neuropathic pain in the shoulder and upper arm, lasting
    around four weeks on average. This phase is the therapeutic window for corticosteroids.
  evidence:
  - reference: PMID:16371410
    reference_title: "The clinical spectrum of neuralgic amyotrophy in 246 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generally, the course of the pain manifests itself in three consecutive phases with an initial severe, continuous pain lasting for approximately 4 weeks on average."
    explanation: >-
      Establishes both the three-phase structure and the duration of the first phase, in the
      largest series of this disease.
- phase: Paresis phase
  notes: >-
    As the initial pain subsides, patchy flaccid paresis and amyotrophy appear in the affected
    nerve distributions, most often upper and middle trunk.
  evidence:
  - reference: PMID:16371410
    reference_title: "The clinical spectrum of neuralgic amyotrophy in 246 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We investigated the symptoms, course and prognosis of neuralgic amyotrophy (NA) in a large
      group of patients with idiopathic neuralgic amyotrophy (INA, n = 199) and hereditary neuralgic
      amyotrophy (HNA, n = 47) to gain more insight into the broad clinical spectrum of the
      disorder. ... Generally, the course of the pain manifests itself in three consecutive phases
      with an initial severe, continuous pain lasting for approximately 4 weeks on average. Sensory
      involvement was quite common and found in 78.4% of patients but was clinically less impairing
      than the initial pain and subsequent paresis. As a typically patchy disorder NA can affect
      almost any nerve in the brachial plexus, although damage in the upper and middle trunk
      distribution with involvement of the long thoracic and/or suprascapular nerve occurred most
      frequently (71.1%).
    explanation: >-
      Identifies neuralgic amyotrophy, initial pain followed by paresis and the common patchy
      upper/middle-trunk nerve distribution.
- phase: Residual phase
  notes: >-
    Slow and often incomplete recovery. This is the phase the modern rehabilitation approach
    targets, and the phase whose burden the older literature understated.
  evidence:
  - reference: PMID:16371410
    reference_title: "The clinical spectrum of neuralgic amyotrophy in 246 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall recovery was less favourable than usually assumed, with persisting pain and paresis in approximately two-thirds of the patients who were followed for 3 years or more."
    explanation: >-
      The prognosis correction that underpins this entry's treatment section. Two-thirds with
      persisting symptoms at three years is the reason rehabilitation is curated as
      disease-modifying rather than supportive.
treatments:
- name: High-Dose Oral Corticosteroids
  description: >-
    A short trial of high-dose oral corticosteroids in the acute phase, advised for patients
    seen early while still in pain. The aim is to damp the inflammatory attack during the window
    in which it is still active.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  notes: >-
    Bound to CHEBI:50858 rather than the NCIT Corticosteroid term. NCIT:C2322 does resolve to
    "Corticosteroid", but it is not reachable from NCIT:C1909 and so fails the
    ChemicalEntityTerm dynamic enum: NCIT classifies corticosteroids under Hormone rather
    than Pharmacologic Substance, so the enum's NCIT:C1909 root cannot reach them
    (dismech#10978).
  target_mechanisms:
  - target: Multifocal Inflammatory Attack on Peripheral Nerve
    description: Suppresses the acute inflammatory attack on the nerve during the painful phase.
    evidence:
    - reference: PMID:19321467
      reference_title: "Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The median time until initial pain relief was lower in the study group (12.5 days vs 20.5 days), and a significantly higher percentage already recovered strength in the first month of treatment (18% vs 6.3%; p = 0.011)."
      explanation: >-
        The comparative data behind the recommendation: 50 treated patients against a historical
        control group of 203 untreated ones. A retrospective case series with a historical
        control is weak for causal attribution, and the authors say so themselves - they
        recommend the regimen "pending a prospective, randomised trial verifying the results".
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If patients are seen early and are still in pain, a short trial of high-dose oral corticosteroids is advised"
    explanation: States the recommendation and the timing constraint on it.
  - reference: PMID:32487526
    reference_title: "Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment options were confined to application of corticosteroids and symptomatic management, without proven positive effects on long-term outcomes"
    explanation: >-
      Refutes a long-term outcome benefit for corticosteroids. Recorded alongside the
      recommendation because the two claims are both true and about different endpoints: acute
      phase practice versus proven long-term effect.
- name: Intravenous Immunoglobulin
  description: >-
    Immunomodulating treatment in the acute phase, cited alongside steroids as potentially
    beneficial. Early immunomodulation is presented as important for optimal recovery.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Multifocal Inflammatory Attack on Peripheral Nerve
    description: Immunomodulation directed at the acute immune attack on the nerve.
  evidence:
  - reference: PMID:34054111
    reference_title: "Neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute phase treatment of NA with steroids or i.v. immunoglobulin may benefit patients."
    explanation: >-
      Names IVIG as an acute-phase option. The hedged "may benefit" is the strength of the claim
      and is not upgraded here.
- name: Peripheral Nerve Surgery
  description: >-
    Surgical treatment of hourglass constrictions and nerve torsion identified on
    high-resolution imaging. This is the treatment that the structural findings made possible,
    and it applies to the constriction subgroup rather than to neuralgic amyotrophy generally.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Peripheral nerve surgery for hourglass constriction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Focal Nerve Constriction and Torsion
    description: >-
      Addresses the focal structural lesion directly, by neurolysis, resection or grafting of
      the constricted segment.
  evidence:
  - reference: PMID:32487526
    reference_title: "Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "surgery has shown to improve clinical outcomes in such cases, indicating the viability of peripheral nerve surgery as a valuable treatment option in NA"
    explanation: Supports surgery for the imaging-identified constriction subgroup specifically.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prognosis is generally favorable after surgery, with a high rate of good motor recovery."
    explanation: Independent statement of post-surgical outcome in the constriction subgroup.
  - reference: PMID:32868098
    reference_title: "Outcomes of Microneurolysis of Hourglass Constrictions in Chronic Neuralgic Amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine of 11 operative patients experienced clinical recovery compared with 3 of 13 nonsurgical patients."
    explanation: >-
      The comparative outcome behind the recommendation, quoted as counts rather than as a
      percentage because the arms are 11 and 13 patients. The paper grades itself Therapeutic
      IV, and allocation was not randomised, so this establishes an association between surgery
      and recovery in a selected group, not an effect size.
- name: Phrenic Nerve Reconstruction
  description: >-
    Surgical repair of the injured phrenic nerve for symptomatic diaphragm paralysis, in
    selected patients. Curated because diaphragmatic weakness is a phenotype of this entry with
    no other treatment linked to it, and because it is the intervention that follows from the
    HEV-associated phrenic presentation.

    The evidence is weaker than for the other surgical entry here: this is a narrative review of
    phrenic nerve reconstruction across all causes of phrenic injury, of which neuralgic
    amyotrophy is one, not a series of NA patients. It reports no NA-specific outcome.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Phrenic nerve reconstruction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Diaphragmatic weakness
    description: >-
      Restores functional diaphragmatic activity by repairing the nerve lesion, rather than
      compensating for it mechanically as diaphragm plication does.
  evidence:
  - reference: PMID:36031309
    reference_title: Phrenic nerve paralysis and phrenic nerve reconstruction surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common etiologies of phrenic injuries include cervical trauma, iatrogenic injury in the neck or chest, and neuralgic amyotrophy."
    explanation: >-
      Establishes that neuralgic amyotrophy is among the phrenic injuries this operation is
      performed for, which is what makes the treatment in scope for this entry.
  - reference: PMID:36031309
    reference_title: Phrenic nerve paralysis and phrenic nerve reconstruction surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical repair of the nerve injury to restore functional diaphragmatic activity, termed phrenic nerve reconstruction, is a safe and effective alternative to static repositioning of the diaphragm (diaphragm plication), in properly selected patients."
    explanation: >-
      The efficacy claim, with the authors' own restriction to "properly selected patients"
      preserved. A review statement, not a trial result.
- name: Scapular Coordination Rehabilitation
  description: >-
    Multidisciplinary rehabilitation focused on scapular coordination, energy distribution
    strategies and self-management. Because persisting symptoms are attributed to reduced nerve
    endurance and an altered movement pattern rather than to axon loss, this targets the actual
    driver of long-term disability and is not merely supportive.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  target_mechanisms:
  - target: Reduced Nerve Endurance and Maladaptive Motor Pattern
    description: >-
      Retrains scapular coordination and paces energy expenditure, addressing the movement
      pattern and endurance limitation that carry the persisting symptoms.
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Persistent complaints are common, and a multidisciplinary rehabilitation approach focusing on scapular coordination, energy distribution strategies, and self-management is indicated."
    explanation: States the indication and the specific content of the rehabilitation programme.
  - reference: PMID:34054111
    reference_title: "Neuralgic amyotrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients benefit from specific rehabilitation treatment."
    explanation: Independent statement of benefit from targeted rehabilitation.
  - reference: PMID:36697215
    reference_title: "Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean group difference adjusted for sex, age and SRQ-DLV baseline score was 8.60 (95%CI: 0.26 to 16.94, p=0.044)."
    explanation: >-
      The primary outcome of the only randomised trial of this intervention, and the strongest
      interventional evidence in this disease. Note the confidence interval nearly touches zero
      and the trial randomised 47 patients but analysed 37 after dropout, so the effect is real
      but imprecise.
  - reference: PMID:36697215
    reference_title: "Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proportion attaining a minimal clinically relevant SRQ-DLV improvement (\u226512) was larger for the MR group (59%) than the UC group (33%) with a number needed to treat of 4."
    explanation: >-
      The responder analysis, which is what makes the effect interpretable: a number needed to
      treat of 4 on a clinically anchored threshold rather than a group mean on a scale.
  - reference: PMID:39402917
    reference_title: "Neuralgic amyotrophy: An update in evaluation, diagnosis, and treatment approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rather than strength training which may worsen the symptoms"
    explanation: >-
      The explicit negative that defines the intervention by contrast. Curated because the
      obvious rehabilitation approach to a weak limb is the wrong one here, and an entry that
      records only what to do leaves that trap in place.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:34054111
      reference_title: "Neuralgic amyotrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an auto-immune multifocal peripheral nervous system disorder that leaves many patients permanently impaired if not recognized and treated properly"
      explanation: Places the disorder among the peripheral nervous system diseases.
diagnosis:
- name: Clinical diagnosis with exclusion of alternative causes
  description: >-
    Neuralgic amyotrophy is diagnosed clinically. Ancillary studies are used to exclude
    infectious or malignant causes or to assess a differential diagnosis, rather than to confirm
    the disease. High-resolution ultrasound and MRI have a distinct role: identifying hourglass
    constrictions or nerve torsion pre-surgically, which changes management for that subgroup.
  evidence:
  - reference: PMID:26662794
    reference_title: "Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NA is a clinical diagnosis, and ancillary studies serve to exclude infectious or malignant causes or to assess a differential diagnosis."
    explanation: States the diagnostic model and the limited role of ancillary testing.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is now widely accepted that nerve imaging is necessary in identifying hourglass constrictions/nerve torsion pre-surgically in patients with an acute mononeuropathy/plexopathy."
    explanation: Establishes the specific, surgical role of nerve imaging.
  - reference: PMID:36214185
    reference_title: Imaging of neuralgic amyotrophy in the acute phase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "US and MRN showed nerve abnormalities within 1 mo from NA onset in 90% of patients."
    explanation: >-
      Puts a number on the imaging claim above. 39 patients imaged within 31 days of onset, so
      this is the yield in the acute window specifically, not in a chronic presentation.
  - reference: PMID:36214185
    reference_title: Imaging of neuralgic amyotrophy in the acute phase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HGCs were found in 74% (29/39) of the patients: 4 within 1 wk, 8 within 2 wk, 5 within 3 wk, and 12 within 4 wk."
    explanation: >-
      The constriction yield and its timing, which is the operationally useful part: the earliest
      appeared within 12 hours on ultrasound, so a normal early scan does not exclude them and a
      repeat within the month is what the distribution supports.
- name: Hepatitis E serology in phrenic or diaphragmatic involvement
  description: >-
    Test for HEV IgM and IgG with serum HEV RNA when the phrenic nerve or diaphragm is involved.
    This is the action that follows from the observation curated in the environmental section:
    the reason HEV-associated cases are missed is that liver enzymes are normal by the time the
    neuropathy presents, so nothing prompts the serology unless it is asked for on the
    neurological picture alone.

    The recommendation is stated at a lower level of confidence than the imaging above. It rests
    on two small uncontrolled series, plus the case-control study's suggestion to test acute-phase
    patients where there is bilateral involvement or hepatitis. No study has evaluated this as a
    diagnostic strategy, so its yield is unknown.
  evidence:
  - reference: PMID:38657646
    reference_title: "Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, even in diaphragmatic dysfunction without NA symptoms and causative damaging event, HEV infection should be considered, as it may represent a subform of NA with only phrenic nerve involvement."
    explanation: >-
      The authors' own recommendation, extending past NA into unexplained diaphragmatic
      dysfunction. Quoted with the hedges ("should be considered", "may represent") intact.
  - reference: PMID:39364568
    reference_title: Immune triggers preceding neuralgic amyotrophy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest to test NA patients in the acute phase for intracellular antigens, especially in the case of concomitant bilateral involvement and hepatitis."
    explanation: >-
      Independent support for testing in the acute phase, from the case-control study, with the
      trigger pattern that should raise suspicion.
discussions:
- discussion_id: hourglass_constriction_same_disease_or_not
  kind: CONTROVERSY
  prompt: >-
    Are neuralgic amyotrophy, hourglass nerve constriction and nerve torsion different
    evolutions of one pathological process, or distinct entities that resemble each other?
  rationale: >-
    This is stated as an open question in the review literature rather than a settled point, and
    it has direct consequences for this entry's structure. If they are one process, the
    constriction node belongs downstream of the inflammatory attack, which is how the pathograph
    currently draws it, and the ultrasound categories - swelling, swelling with incomplete
    constriction, swelling with complete constriction, fascicular entwinement - are stages of a
    continuum. If they are separate entities, that edge is wrong and the constriction cases are
    a different disease that happens to look similar. The node carries
    mechanism_confidence: PROVISIONAL for this reason - causal_link_type records directness, not
    confidence, so it is not the slot that expresses this. The practical stakes are not academic: the constriction subgroup has a poor
    prognosis without surgery and a good one with it, so which patients are considered to have
    "neuralgic amyotrophy" determines who gets referred.
  attaches_to:
  - pathophysiology#Focal Nerve Constriction and Torsion
  - pathophysiology#Multifocal Inflammatory Attack on Peripheral Nerve
  evidence:
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathophysiology of neuralgic amyotrophy, hourglass constriction and nerve torsion is still poorly understood, and a generic role of inflammation is proposed for all these conditions."
    explanation: >-
      States that the shared mechanism is proposed rather than demonstrated, which is the basis
      for recording this as a controversy.
  - reference: PMID:38248282
    reference_title: "Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in some cases of NA, after a first phase characterized by nerve inflammation and swelling, in selected anatomical conditions, the process evolves into hourglass constriction or nerve torsion"
    explanation: >-
      The continuum hypothesis in its explicit form, which is the reading the pathograph
      currently encodes.
📚

References & Deep Research

References

16
PMID:26662794
Neuralgic amyotrophy: An update on diagnosis, pathophysiology, and treatment.
No top-level findings curated for this source.
PMID:34054111
Neuralgic amyotrophy.
No top-level findings curated for this source.
PMID:32487526
Neuralgic amyotrophy: a paradigm shift in diagnosis and treatment.
No top-level findings curated for this source.
PMID:38248282
Neuralgic Amyotrophy and Hourglass Nerve Constriction/Nerve Torsion: Two Sides of the Same Coin? A Clinical Review.
No top-level findings curated for this source.
PMID:8614534
Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis.
No top-level findings curated for this source.
PMID:38657646
Hepatitis E and diaphragmatic dysfunction: Case series and review of the literature.
No top-level findings curated for this source.
PMID:40534221
Neurological Manifestations of HEV Infection: A Rare Phenomenon or an Underrecognized Reality?
No top-level findings curated for this source.
PMID:16371410
The clinical spectrum of neuralgic amyotrophy in 246 cases.
No top-level findings curated for this source.
PMID:19254608
Long-term pain, fatigue, and impairment in neuralgic amyotrophy.
No top-level findings curated for this source.
PMID:36697215
Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial.
No top-level findings curated for this source.
PMID:39402917
Neuralgic amyotrophy: An update in evaluation, diagnosis, and treatment approaches.
No top-level findings curated for this source.
PMID:39364568
Immune triggers preceding neuralgic amyotrophy.
No top-level findings curated for this source.
PMID:19321467
Evaluation of prednisolone treatment in the acute phase of neuralgic amyotrophy: an observational study.
No top-level findings curated for this source.
PMID:36214185
Imaging of neuralgic amyotrophy in the acute phase.
No top-level findings curated for this source.
PMID:32868098
Outcomes of Microneurolysis of Hourglass Constrictions in Chronic Neuralgic Amyotrophy.
No top-level findings curated for this source.
PMID:36031309
Phrenic nerve paralysis and phrenic nerve reconstruction surgery.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

A note on this entry's evidence base, because it is not visible from the evidence items themselves. Sixteen references: five are narrative reviews (PMID:26662794, PMID:32487526, PMID:34054111, PMID:38248282, PMID:39402917) carrying MEDLINE publication type "Review" with no primary patient data of their own, and one (PMID:36031309) is a review of phrenic nerve reconstruction across all causes rather than in this disease. The remaining ten report original human observations, and they carry the load for the entry's quantitative claims: - PMID:36697215 - randomised controlled trial (n=47 randomised, 37 analysed) of the rehabilitation programme, the only randomised evidence in this disease. - PMID:16371410 - 246-patient clinical series, the source of the three-phase course, the sensory-involvement frequency and the two-thirds persisting-symptom prognosis. Note this cohort mixes 199 idiopathic with 47 hereditary cases, while this entry scopes to the acquired form. - PMID:39364568 - prospective matched case-control (n=57) of immune triggers, with central serology. - PMID:19254608 - 89 patients assessed on average two years out, for long-term fatigue. - PMID:36214185 - 39 patients imaged within 31 days, for the imaging yields. - PMID:19321467 - 50 treated patients against a historical control group of 203, for the corticosteroid effect. Retrospective with a historical control, which the authors flag. - PMID:32868098 - 24 patients, non-randomised, for the surgical comparison. Graded Therapeutic IV by its own authors. - PMID:8614534 - the four-patient brachial plexus biopsy series, still the only direct tissue evidence for the immune-mediated mechanism this entry is built on. - PMID:38657646 (13 patients) and PMID:40534221 (2 patients) - the hepatitis E association, both uncontrolled. Every one of these is graded HUMAN_CLINICAL, which is what the schema's definition supports and the dominant convention in this knowledge base. But an RCT, a 246-patient series, a four-patient biopsy series and a two-patient case report all carry that identical value, and a reader cannot tell them apart at the evidence item. That is why the distinctions above are written out here. See dismech#9421 and dismech#9827. A comparative-species model was considered and rejected. The deep-research report for this disease offers feline hypertrophic brachial plexus neuritis (PMID:29925717) as a naturally occurring analogue. Reading the source rather than the summary, that cat had a chronic hypertrophic demyelinating neuritis with onion-bulb formation, which its own authors compare to human CIDP rather than to neuralgic amyotrophy. NA is an acute, painful, multifocal axonal process. The shared feature is brachial plexus inflammation, which is not enough to make it a model of this disease, so it is deliberately not curated as one.

Review round 1 on PR #10998: consume the primary studies the entry's own notes said were missing · 2026-09-04T19:39:41Z · View source

The review's central criticism was correct and is the thing worth recording: this entry's own notes complained that its evidence base was thin because four of seven references were narrative reviews, while the deep-research report committed in the same PR contained the primary studies that fix it. An RCT, a 246-patient series and a prospective matched case-control were sitting in the artifact, unread. Seven of the report's 40 verified references had been used. This is the same defect the NUBPL PR was pulled up on an hour earlier, in a different guise: there, the unread source was a 1,095-line full text mined only for its abstract; here it was a committed report mined for a fraction of its citations. The general form is treating a source as consumed once something has been taken from it. Blocking 1 - Paresthesia frequency was OCCASIONAL (5-29%) on a snippet that carried no frequency at all. Corrected to FREQUENT on PMID:16371410's 78.4% sensory involvement, with the original snippet's explanation rewritten to say explicitly that it supports occurrence and not frequency. Recorded that the 246-patient denominator mixes 199 idiopathic with 47 hereditary cases while this entry scopes to the acquired form, and that the paper reports no separate rate by subtype. Blocking 2 - Fatigue (HP:0012378) added, FREQUENT, and wired DIRECT from the Reduced Nerve Endurance node. It is the clinical readout of this entry's central claim. The second evidence item is the load-bearing one: fatigue does not correlate with residual paresis on the MRC scale, which is the dissociation that separates the endurance model from simple deconditioning and is why the phenotype hangs off that node rather than off axonal injury. Blocking 3 - Rehabilitation cited two review sentences for the intervention this entry argues is disease-modifying. Added PMID:36697215, the only RCT in this disease, with both the adjusted group difference and the responder analysis, and noted that the CI nearly touches zero and 47 randomised became 37 analysed. Added PMID:39402917 for the explicit negative that strength training may worsen symptoms - curated because the obvious rehabilitation approach to a weak limb is the wrong one here, and an entry recording only what to do leaves that trap in place. Blocking 4 - Only hepatitis E was curated as a trigger, and it is the weakest-evidenced one, while the first pathophysiology node depends on a general immune trigger. Added an "Antecedent infection or vaccination" environmental entry from PMID:39364568, the prospective matched case-control with central serology: 26.3% microbiologically confirmed infection, 12.3% COVID-19 vaccination as potential trigger, 38.6% confirmed overall, and the association of acute viral infection with bilateral plexus involvement. The description states that 38.6% means most attacks have no identified trigger, so this is a precipitant and not a necessary cause. HEV remains as the clinically distinctive instance rather than the only one. Blocking 5 - The diagnostic action implied by the HEV finding was absent. Added a "Hepatitis E serology in phrenic or diaphragmatic involvement" diagnosis entry, explicitly at a lower confidence than the imaging entry: it rests on two uncontrolled series plus a suggestion in the case-control study, and no study has evaluated it as a strategy, so its yield is unknown. Suggestions taken: corticosteroid comparative data (PMID:19321467, with the authors' own "pending a prospective, randomised trial" caveat), imaging yields (PMID:36214185, 90% and 74%, with the timing distribution that makes a repeat scan the right response to a normal early one), the surgical comparative series quoted as counts rather than percentages because the arms are 11 and 13 (PMID:32868098, self-graded Therapeutic IV), a three-phase progression section (PMID:16371410), and phrenic nerve reconstruction (PMID:36031309) linked to the diaphragmatic weakness phenotype, which previously had no treatment - flagged in its own description as a review across all causes of phrenic injury with no NA-specific outcome. Suggestion 11 declined: splitting the multifactorial susceptibility node. The node's claim IS the conjunction - that no single factor is sufficient - so splitting it would assert three independent mechanisms the literature does not. Recorded here rather than silently ignored. Suggestion 12 taken: the controversy rationale said "the edge is marked PROVISIONAL"; it is the node's mechanism_confidence. causal_link_type records directness, not confidence. The reviewer resolved the open ECTO question with a working adapter: ECTO genuinely has no hepatitis exposure term. The notes now record a confirmed absence rather than an uninformative search, and name what was searched. The distinction matters - a claim that a term does not exist needs a search behind it, which is the error I made on the concurrent NUBPL PR. The NCIT:C2322 note now points at dismech#10978, which I filed earlier today and which the reviewer had asked be opened; no duplicate was created. The entry's evidence-base note is rewritten. It previously described a seven-reference base that was mostly reviews; there are now sixteen references, ten of them reporting original human observations, and the note lists each with its design and size. The point it makes is unchanged and now sharper: an RCT, a 246-patient series, a four-patient biopsy series and a two-patient case report all carry an identical evidence_source: HUMAN_CLINICAL, and a reader cannot tell them apart at the evidence item. Validation: 54/54 snippets verified, up from 33/33. Schema, terms, entity refs, causal targets, duplicate keys, qualifier terms, enum values and environmental evidence all clean. All seven phenotypes are the target of a downstream edge - checked explicitly, since check-causal-targets does not detect orphans.

Create: Neuralgic Amyotrophy (MONDO:0017362) · 2026-09-04T19:20:32Z · View source

New entry for neuralgic amyotrophy (Parsonage-Turner syndrome), MONDO:0017362. Seven references, 33/33 snippets verified. SCOPE. This entry covers the acquired, idiopathic form only. Hereditary neuralgic amyotrophy, caused by SEPTIN9 duplication, is a separate MONDO concept with a different initiating lesion. MONDO itself supports the split: MONDO:0017362's parent is "acquired peripheral neuropathy". The deep-research report blends the two, and reports the OMIM number for the hereditary form (162100); that is why the entry's scoping is stated explicitly in its description rather than left implicit. The pathograph is built on a three-factor susceptibility model (genetic predisposition, biomechanical vulnerability of the plexus, immune trigger) rather than a single initiating lesion, because that is what the literature supports. All six phenotypes are wired into it. The hourglass nerve constriction question is curated as a CONTROVERSY discussion rather than resolved: whether the constrictions are a cause of the deficit or a consequence of the inflammatory attack is genuinely unsettled, and the entry does not choose. ENVIRONMENTAL TRIGGER. A hepatitis E virus entry is linked to the inflammatory-attack node with environmental_effect TRIGGERS. This is the substantive addition from the deep-research report. It earns curation because the association is clinically distinctive rather than incidental: HEV-associated attacks are enriched for phrenic nerve involvement and diaphragmatic paralysis, and one 13-patient series found normal liver enzymes in every case, which is why the trigger is missed. Two sources, both small and uncontrolled, and the entry says so. exposure_term is bound to ECTO:3000001 (exposure to virus) with "exposure to hepatitis E virus" in preferred_term. Whether ECTO codes hepatitis E exposure specifically is NOT established: the local ECTO index returned nothing for a control query as well as for the real one, so the search was uninformative rather than negative, and the entry's notes say that rather than asserting an absence. This distinction matters - on the concurrent NUBPL PR I asserted an ontology absence I had not checked, and it was false. DELIBERATELY NOT CURATED, both recorded in notes so they are not re-litigated: 1. The feline model. The report offers feline hypertrophic brachial plexus neuritis (PMID:29925717) as a naturally occurring comparative-species analogue. Reading the source rather than the summary, that cat had a chronic hypertrophic DEMYELINATING neuritis with onion-bulb formation, which its own authors compare to human CIDP. NA is an acute, painful, multifocal AXONAL process. Shared brachial plexus inflammation is not enough to make it a model of this disease. 2. Module conformance. peripheral_axonal_degeneration was checked and does not fit: it scopes to length-dependent distal degeneration, while NA is multifocal and proximal. No conforms_to is asserted. TERM DISCIPLINE. No CURIE in this entry came from the report, and the report's own Term Validation section shows why that matters: 8 of its 23 checked terms name a different concept, including every treatment term it proposed - NCIT:C198 "Prednisone" is Acetaminophen, NCIT:C1409 "Corticosteroid" is Carbenicillin Indanyl Sodium, NCIT:C579 "Immunoglobulin therapy" is Inorganic Chemical, NCIT:C15296 "Physical Therapy" is Isolated Chemotherapeutic Perfusion, UBERON:0001824 "brachial plexus" is mucosa of larynx, UBERON:0001379 "deltoid" is vastus lateralis. UBERON:0003732 "phrenic nerve" does not exist. The report also proposed MONDO:0100053 for this disease, which is anaphylaxis; the entry uses MONDO:0017362 from the stub, verified against the ontology. EVIDENCE BASE. Recorded in the entry's notes because it is not visible from the evidence items: four of the seven references are narrative reviews carrying MEDLINE publication type "Review", three report original human observations (a four-patient biopsy series and two small HEV series). All seven are graded HUMAN_CLINICAL, which is the schema's definition and the KB's dominant convention, but a reader cannot tell a review from a biopsy series at the evidence item. See dismech#9421.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 40 citations 2026-09-04T19:12:56.706886

1. Disease Information

Overview. Neuralgic Amyotrophy is an uncommon-to-underrecognized peripheral nervous-system disorder characterized by episodes ("attacks") of extreme neuropathic pain followed by rapid, multifocal, patchy weakness and atrophy predominantly in the upper limbs. In its classic presentation it is a brachial plexopathy or multifocal motor-predominant neuropathy with a monophasic course, though sensory involvement is common and extra-plexus nerves are frequently affected.

Key identifiers (as commonly catalogued): - MONDO: MONDO:0100053 (neuralgic amyotrophy) — suggested; confirm in current release - OMIM: 162100 (Neuralgic amyotrophy / hereditary brachial plexus neuropathy, HNA) - Orphanet: ORPHA:2901 (Neuralgic amyotrophy) - ICD-10: G54.5 (Neuralgic amyotrophy) - ICD-11: 8B93 / brachial plexus disorder region (neuralgic amyotrophy) - MeSH: D020968 (Brachial Plexus Neuritis) - Gene (HNA): SEPT9 / SEPTIN9, HGNC:7323, chromosome 17q25

Synonyms and alternative names: Parsonage–Turner syndrome; brachial plexus neuritis; brachial neuritis; brachial neuralgic amyotrophy; idiopathic brachial plexopathy; acute brachial neuropathy; hereditary brachial plexus neuropathy (HBPN, hereditary form); shoulder-girdle syndrome. Parsonage and Turner unified previously separate descriptions under the term "neuralgic amyotrophy" in 1948, highlighting the combination of neuropathic pain and muscular atrophy (PMID: 39070412).

Source of information. The knowledge in this report is derived from aggregated disease-level resources — cohort studies, case-control studies, clinical reviews, and case reports/series — rather than individual EHR extraction. The largest supporting cohort comprised 246 patients (PMID: 16371410).

2. Etiology

Disease causal factors. NA is a complex disease arising from the interaction of genetic predisposition, mechanical vulnerability, and immune-mediated triggering. There is no single cause; rather, the current, well-supported model is a triad (PMID: 21556032):

"The disease is thought to result from an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus (possibly representing disturbance of the epineurial blood-nerve barrier), and an immune or autoimmune trigger for the attacks."

Genetic risk factors. In the hereditary form (HNA), SEPT9 point mutations and duplications on 17q25 are causal in ~55% of families (see Section 4). SEPT9 variants have also been linked to a broader phenotypic spectrum, including a Charcot–Marie–Tooth-like presentation (PMID: 32122354). In idiopathic NA, a genetic susceptibility is inferred but not molecularly defined; recurrence and family history predict a discoverable genetic cause (PMID: 30560241).

Environmental / triggering risk factors. Attacks are frequently preceded by immunologically active events: - Infection — the single most-cited category; HEV genotype 3 is a recurrent, characteristic trigger (Section 5). - Vaccination — COVID-19 mRNA and viral-vector vaccines; also post-exposure prophylaxis and influenza vaccine (PMID: 38543940; PMID: 25098693). - Surgery, trauma, childbirth/peripartum period, strenuous exercise, cold, and psychological stress (PMID: 21556032; PMID: 31619932). - Age and sex — idiopathic NA typically presents in adulthood (mean ~41 years) with a male predominance; hereditary NA presents earlier (mean ~28 years).

Protective factors. No genetic or environmental protective factors have been established in the literature reviewed. This is a genuine knowledge gap. Prophylactic corticosteroids or IVIG may reduce surgical- or childbirth-induced attacks in HNA, functioning as a preventive (not naturally protective) intervention (PMID: 38176820).

Gene–environment interactions. The triad model is itself a gene–environment interaction: an immune trigger acting upon a genetically/mechanically predisposed plexus precipitates the focal neuritis. In HNA, external stimuli (infections, vaccinations, cold, stress, surgery, exercise) provoke recurrent attacks on the SEPT9-predisposed background (PMID: 31619932).

3. Phenotypes

NA's phenotype evolves through three consecutive pain phases, beginning with an initial severe, continuous pain lasting approximately 4 weeks on average (PMID: 16371410):

"the course of the pain manifests itself in three consecutive phases with an initial severe, continuous pain lasting for approximately 4 weeks on average. Sensory involvement was quite common and found in 78.4% of patients"

Phenotype Type HPO suggestion Frequency / characteristics
Severe shoulder/arm neuropathic pain Symptom HP:0012532 (Chronic pain) / HP:0003326 (Myalgia); neuropathic pain Near-universal at onset; acute, continuous ~4 weeks
Multifocal muscle weakness/paresis Clinical sign HP:0003484 (Upper limb muscle weakness) Follows pain; patchy, motor-predominant
Muscle atrophy Physical manifestation HP:0003202 (Skeletal muscle atrophy) Common; early
Sensory loss/paresthesia Symptom/sign HP:0003390 (Sensory neuropathy) / HP:0003401 (Paresthesia) 78.4%
Scapular winging / dyskinesia Clinical sign HP:0003691 (Scapular winging) >60% residual (Sections 6/11)
Phrenic nerve palsy / diaphragmatic paralysis Clinical sign HP:0002094 (Dyspnea); diaphragmatic paralysis Subset, esp. HEV-associated; orthopnea
Fatigue Symptom HP:0012378 (Fatigue) ~1/3 long-term

Distribution. The upper/middle trunk pattern — long thoracic and/or suprascapular nerve — is most frequent (71.1%) (PMID: 16371410). Involvement is typically unilateral and asymmetric, though bilateral involvement occurs, particularly after acute viral infection.

Age of onset, severity, progression. Onset is predominantly adult in INA (mean 41.3 yrs) and earlier in HNA (mean 28.4 yrs), spanning infancy to adulthood (PMID: 16371410; PMID: 31619932). Severity is variable; the course is classically monophasic/episodic, with recurrence in 26.1% of INA over ~6-year follow-up and a mean of 3.5 attacks in HNA versus 1.5 in INA.

Quality-of-life impact. About a quarter to a third of patients report significant long-term pain and fatigue, and half to two-thirds experience persistent impairments in daily life; symptoms correlate with residual shoulder/arm dysfunction rather than psychological distress (PMID: 19254608).

4. Genetic / Molecular Information

Causal gene. Hereditary NA is autosomal dominant and associated with a point mutation or duplication in SEPT9 (SEPTIN9) on chromosome 17q25 in 55% of affected families (PMID: 21556032):

"in 55% of affected families, neuralgic amyotrophy is associated with a point mutation or duplication in the SEPT9 gene on chromosome 17q25"

  • Gene: SEPT9 / SEPTIN9, HGNC:7323, OMIM *604061; HNA phenotype OMIM #162100.
  • Variant types: missense point mutations (e.g., p.Arg106Trp / R106W), intragenic duplications (including duplication of exon 2), and CNVs. Classification: pathogenic/likely pathogenic per ACMG in segregating families.
  • Population frequency: rare; HNA is a rare Mendelian disorder. Specific gnomAD allele frequencies were not established in the reviewed literature.
  • Origin: germline, autosomal dominant.

Functional consequences. SEPT9 mediates septin binding to microtubules. HNA mutations impair this function (PMID: 34854883):

"HNA mutations abrogate this association, identifying a putative regulatory domain"

A MAP-like motif unique to septin-9 isoform 1 drives septin octamer–microtubule interaction, and HNA mutations abrogate this. Molecular-dynamics simulation shows the mutation significantly alters septin-9 conformation, impairing microtubule binding and bundling (PMID: 39428775):

"Molecular simulation study has revealed that the mutation has significantly altered the conformation of septin-9 protein, thereby impairing the microtubule binding and bundling ability"

This constitutes a loss/alteration of function in cytoskeletal regulation (cytokinesis, membrane trafficking, stress-fiber tuning).

Phenotype extensions. SEPT9 variants can produce dysmorphic features (hypotelorism, cleft palate, long nasal bridge, hypertelorism, epicanthal folds), and a childhood-onset family showed platelet dysfunction (reduced ADP/epinephrine-induced aggregation, impaired δ-secretion) and kidney cysts alongside an exon-2 duplication (PMID: 30019529; PMID: 40852410).

Modifier genes / epigenetics / chromosomal abnormalities. No modifier genes, disease-specific epigenetic marks, or large-scale chromosomal abnormalities have been established for NA in the reviewed literature — genuine knowledge gaps.

Suggested ontology terms: Gene HGNC:7323 (SEPTIN9); GO:0005819 (spindle), GO:0000910 (cytokinesis), GO:0008017 (microtubule binding).

5. Environmental Information

Environmental / infectious triggers. Immune events preceding NA are well documented. In a prospective matched case-control study (n=57), a symptomatic infectious trigger confirmed microbiologically preceded NA in 26.3% of patients, and COVID-19 vaccination was a potential trigger in 12.3% (PMID: 39364568):

"NA onset was preceded by a symptomatic infectious trigger confirmed by microbiological tests in 15/57 (26.3%) patients. Coronavirus disease 2019 vaccination was considered a potential trigger in 7/57 (12.3%) subjects. An acute viral infection was associated with a bilateral involvement of the brachial plexus (p = 0.003, Cramèr's V = 0.43)"

Hepatitis E virus (HEV, genotype 3) is a recurrently reported and clinically distinctive trigger, characteristically causing NA with phrenic nerve involvement and diaphragmatic paralysis (PMID: 40534221; PMID: 38657646):

"Electromyography showed severe bilateral phrenic nerve involvement. The diagnosis of neuralgic amyotrophy with diaphragmatic paralysis secondary to HEV was made"

"NA that shows involvement of the phrenic nerve resulting in diaphragmatic dysfunction and dyspnoea, may be associated with HEV infection"

Agents tested/reported in NA workups include HEV, HIV, SARS-CoV-2, EBV, CMV, parvovirus B19, VZV, Borrelia, Mycoplasma, and Bartonella. Livestock-associated HEV exposure has been implicated (PMID: 35379662).

Occupational/toxic factors. A rare report links epidemic dropsy (argemone-oil-adulterated mustard oil) with brachial neuritis, but toxic causes are not a recognized major etiology (PMID: 22231775).

Lifestyle factors. Strenuous physical exercise and unaccustomed exertion of the shoulder girdle are reported precipitants; smoking/diet/alcohol are not established risk factors.

Suggested ontology term: NCBI Taxonomy Orthohepevirus A (HEV).

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Genetic predisposition (SEPT9 mutation in HNA; undefined susceptibility in INA) → leads to an intrinsically vulnerable brachial plexus, plausibly via altered septin–microtubule cytoskeletal regulation in nerve/supporting cells (tissue-level mechanism inferred, not fully demonstrated).
  2. Predisposition plus a mechanical susceptibility of the plexus — possibly a disturbed epineurial blood–nerve barrier — results in a nerve segment prone to immune access and injury (PMID: 21556032).
  3. An immune/autoimmune trigger (infection—especially HEV—vaccination, surgery, trauma, childbirth, exercise) activates a focal immune response directed at the brachial plexus (PMID: 39364568).
  4. The immune response produces multifocal mononuclear inflammatory-cell infiltration of nerve fascicles (demonstrated on biopsy) (PMID: 8614534).
  5. Inflammation and focal swelling lead to the pathognomonic hourglass-like constriction / nerve torsion at vulnerable segments, with proximal/distal thickening (PMID: 36214185; PMID: 38248282).
  6. Focal constriction and axonal injury cause the acute severe neuropathic pain (phase 1).
  7. Axonal degeneration results in multifocal flaccid paresis, muscle atrophy, and sensory loss (phase 2), branching by nerve territory:
  8. Long thoracic/suprascapular → scapular winging and dyskinesia.
  9. Phrenic nerve → diaphragmatic paralysis, orthopnea, respiratory failure (branch strongly associated with HEV).
  10. Incomplete axonal regeneration and compensatory abnormal motor control lead to chronic scapular dyskinesia, residual weakness, pain, and fatigue (phase 3) (PMID: 36697215).
SEPT9 mutation / susceptibility  ─┐
Mechanical vulnerability          ─┼──► predisposed plexus segment
(blood–nerve barrier disturbance) ─┘             │
                                 ▼
Immune trigger (HEV, vaccine, surgery, exercise…)
                                 │
                                 ▼
Multifocal mononuclear inflammatory infiltrate
                                 │
                                 ▼
Hourglass constriction / nerve torsion + axonal injury
          │                          │
          ▼                          ▼
  Acute neuropathic pain (~4 wk)   Patchy paresis / atrophy / sensory loss
                                 │
    ┌────────────────────────────┼───────────────────────┐
    ▼                            ▼                        ▼
Long thoracic/suprascapular     Phrenic nerve            Other plexus/extra-plexus
→ scapular winging/dyskinesia   → diaphragm paralysis    → multifocal deficits
                          (HEV-linked)
                                 │
                                 ▼
Incomplete regeneration + abnormal motor control → chronic disability

Molecular pathways / protein dysfunction. Upstream: SEPT9 loss of microtubule-binding/bundling disrupts cytoskeletal regulation (cytokinesis, membrane trafficking, stress fibers) (PMID: 34854883; PMID: 39428775). Downstream: an inflammatory-immune cascade drives the attack.

Cellular processes / immune involvement. The core downstream mechanism is inflammation with mononuclear (lymphocytic/macrophage) infiltration and axonal degeneration (PMID: 8614534):

"There were florid multifocal mononuclear inflammatory cell infiltrates. Present evidence suggests that these brachial neuropathies have an immune basis"

Tissue damage mechanisms. Focal constriction/torsion with ischemic and mechanical axonal injury; denervation muscle edema is seen on MRN in 91% of acute cases (PMID: 36214185).

Cell types and biological processes (ontology suggestions): - GO:0006954 (inflammatory response); GO:0002250 (adaptive immune response) — biological processes. - GO:0008017 (microtubule binding), GO:0000910 (cytokinesis) — SEPT9 molecular function/process. - CL:0000101 (sensory neuron); CL:0011001 (spinal cord motor neuron); CL:0002573 (Schwann cell); CL:0000235 (macrophage); CL:0000542 (lymphocyte) — cell types.

Molecular profiling specific to NA nerve tissue (transcriptomics, proteomics, metabolomics, single-cell, spatial, CRISPR/RNAi screens) was not available in the reviewed literature — a substantial knowledge gap.

7. Anatomical Structures Affected

Organ / system level. Primary target: the peripheral nervous system, specifically the brachial plexus and its branches (long thoracic, suprascapular, axillary, musculocutaneous, radial, median nerves). Secondary involvement: the respiratory system via phrenic nerve → diaphragm; the musculoskeletal system (shoulder girdle) via denervation atrophy and dyskinesia.

Nerve territories. Upper/middle trunk pattern (long thoracic and/or suprascapular) is most frequent (71.1%) (PMID: 16371410). Extra-plexus nerves are commonly involved, more so in HNA (55.8% vs 17.3% in INA). Lesions distal to the brachial plexus (e.g., median nerve, mimicking carpal tunnel) can occur in HNA (PMID: 37587058).

Tissue / cell level. Peripheral nerve tissue (axons, Schwann cells, epineurium/perineurium) and skeletal muscle (secondary denervation atrophy and edema). Inflammatory infiltrate composed of mononuclear cells.

Subcellular level. SEPT9 dysfunction implicates the microtubule cytoskeleton (GO:0005874) and associated stress fibers; axonal transport machinery is plausibly affected (inferred).

Localization and lateralization. Predominantly unilateral and asymmetric; bilateral involvement occurs, associated with acute viral infection (p=0.003) and characteristically with HEV-linked phrenic disease (PMID: 39364568; PMID: 40534221).

Suggested UBERON/CL terms: UBERON:0001824 (brachial plexus); UBERON:0003732 (phrenic nerve); UBERON:0001134 (skeletal muscle tissue); UBERON:0001379 (deltoid); CL:0000101 (sensory neuron); CL:0002573 (Schwann cell).

8. Temporal Development

Onset. Typically adult-onset (INA mean 41.3 yrs) but ranges from infancy to old age; HNA onsets earlier (mean 28.4 yrs) and may present in early childhood (e.g., age 2–9 yrs) (PMID: 16371410; PMID: 30019529; PMID: 40852410). Onset pattern is acute/subacute — sudden severe pain within hours to two weeks.

Progression (three-phase course): 1. Acute pain phase — severe continuous pain, ~4 weeks average. 2. Paresis phase — as pain subsides, patchy weakness, atrophy, sensory loss emerge. 3. Recovery/chronic phase — slow recovery over months to years; frequently incomplete.

Course pattern. Classically monophasic/episodic; recurrence in INA is 26.1% over ~6 years, higher in HNA (mean 3.5 attacks). Serratus anterior winging from NA resolves spontaneously within 3 years in a substantial fraction, but no full recovery was seen if winging persisted beyond 3 years (PMID: 33675974).

Critical windows. Early corticosteroid administration (first month) shortens pain and improves recovery (PMID: 19321467). Surgical neurolysis is considered after 6–12 months of non-recovery (PMID: 32868098). Imaging abnormalities appear early — as early as 12 h on ultrasound and ~3 days on MRN.

9. Inheritance and Population

Epidemiology. Historically considered rare, NA's true incidence is ~1 per 1,000 per year (PMID: 33823638):

"its actual incidence rate is about 1 per 1000 per year"

Combined INA + HBPN incidence has been cited as 3–100 per 100,000 persons per year (PMID: 38176820). Most cases are diagnosed late or not at all.

Inheritance (HNA). Autosomal dominant, caused by SEPT9 mutations/duplications in ~55% of families. Features consistent with: - Incomplete/variable penetrance and variable expressivity — inferred from wide intrafamilial clinical variability (e.g., R106W pedigrees) (PMID: 39428775; PMID: 42644177). - Anticipation, germline mosaicism, founder effects, consanguinity, carrier frequency — not established in the reviewed literature (knowledge gaps).

Demographics. INA shows a male predominance; HNA affects both sexes. Post-COVID-vaccination PTS occurred more frequently in males (61.1% mRNA; 83.3% viral vector) (PMID: 38543940). No strong ethnic or geographic clustering is established, though HNA families are reported across diverse populations (Lebanese, Chinese, Italian, German, Turkish).

INA vs HNA comparison:

Feature Idiopathic (INA) Hereditary (HNA)
n (reference cohort) 199 47
Mean age at onset 41.3 yrs 28.4 yrs
Mean number of attacks 1.5 3.5
Extra-plexus involvement 17.3% 55.8%
Genetic cause undefined SEPT9 (~55% of families)
Outcome better poorer

Source: PMID: 16371410.

10. Diagnostics

Diagnosis is clinical and one of exclusion (PMID: 32140911):

"The diagnosis is clinical, through a comprehensive history and neurological examination"

Conditions to exclude: cervical radiculopathy, rotator cuff tear, CIDP, compressive plexopathy, and neurolymphomatosis (recurrent "attacks" can herald B-cell lymphoma) (PMID: 30560241).

Electrodiagnostics (EMG/NCS). Show multifocal axonal denervation (fibrillations in ~73%), confirming the pattern and distribution.

Imaging — the modern confirmatory pillar. High-resolution ultrasound and MR neurography detect nerve abnormalities in ~90% of patients within one month, including hourglass constrictions in 74% and denervation muscle edema on MRN in 91% (PMID: 36214185):

"US and MRN showed nerve abnormalities within 1 mo from NA onset in 90% of patients. HGCs were found in 74% (29/39) of the patients"

Gadolinium-enhanced MRI/MRN help confirm the diagnosis and guide treatment (PMID: 33823638):

"Gadolinium-enhanced magnetic resonance imaging and high-resolution magnetic resonance neurography are useful for confirming the diagnosis and choosing the appropriate treatment"

Diaphragm ultrasound improves detection of phrenic involvement (PMID: 38176820).

Laboratory / biomarkers. No specific serum biomarker exists. HEV serology (IgM/IgG plus serum HEV RNA) and transaminases should be checked, especially with phrenic/diaphragmatic involvement, to identify a treatable trigger. CSF may show albuminocytological dissociation in vaccine-associated cases.

Genetic testing. SEPT9 single-gene testing (sequencing plus copy-number/duplication analysis) confirms HNA; WES/WGS is useful in atypical or pediatric cases (PMID: 42644177; PMID: 40852410). Indicated with recurrent attacks, family history, early onset, or dysmorphic features.

Differential diagnosis (distinguishing features): cervical radiculopathy (dermatomal, neck-movement-related), rotator cuff pathology (mechanical, no denervation), CIDP (symmetric, demyelinating, chronic), compressive plexopathy/neoplasm (progressive, mass), hereditary neuropathy with liability to pressure palsies.

11. Outcome / Prognosis

Prognosis is guarded, contrary to older "benign self-limited" characterizations (PMID: 38835178):

"The prognosis of untreated NA is poor, with 25% of patients remaining unable to work at three years. The main form of treatment is with corticosteroids that are administered as early as possible"

Morbidity and function. Over 60% of patients have residual complaints and functional limitations, correlated with scapular dyskinesia (PMID: 36697215):

"leading to severe pain and multifocal paresis resulting in >60% of patients having residual complaints and functional limitations correlated with scapular dyskinesia"

About a quarter to a third report significant long-term pain and fatigue; half to two-thirds retain impairments; symptoms are not correlated with residual MRC-scale paresis or psychological distress but with mechanical shoulder/arm dysfunction (PMID: 19254608).

Mortality. NA is not directly fatal, but bilateral diaphragmatic paralysis (e.g., HEV-associated or severe PTS) can cause hypercapnic respiratory failure requiring ventilatory support (PMID: 41428787).

Recovery potential. Slow recovery over months to years; many never achieve full recovery. Serratus anterior winging resolves spontaneously within 3 years in some but not if it persists beyond 3 years (PMID: 33675974). Surgical neurolysis rescues motor function in chronic HGC cases (Section 12).

Prognostic factors. Hereditary form, extra-plexus involvement, greater winging severity, comorbidity, and delayed treatment predict worse outcomes. No validated molecular prognostic biomarker exists.

12. Treatment

Pharmacotherapy (acute phase). Corticosteroids (oral prednisolone/prednisone; high-dose pulsed steroids) given as early as possible shorten the initial pain and may accelerate recovery in some patients (PMID: 19321467):

"The median time until initial pain relief was lower in the study group (12.5 days vs 20.5 days), and a significantly higher percentage already recovered strength in the first month of treatment (18% vs 6.3%; p = 0.011)"

The Cochrane review found no randomized trials but concluded open-label evidence supports early oral prednisone shortening initial pain (PMID: 19588414). Adjunct non-narcotic analgesics for neuropathic pain; opioids are generally avoided. NCIT suggestions: NCIT:C769 (Prednisolone), NCIT:C198 (Prednisone), NCIT:C1409 (Corticosteroid).

Immunotherapy. In pediatric NA, immunotherapy (IVIG/steroids) appears effective, with improvement continuing over one year (PMID: 32228355). Prophylactic steroids or IVIG may reduce surgery- or childbirth-induced attacks in HNA (PMID: 38176820). NCIT:C579 (Immunoglobulin therapy).

Etiologic treatment. When HEV is the trigger, recognition allows targeted management/monitoring and respiratory support.

Surgical / interventional. Microsurgical epineurolysis and perineurolysis of hourglass constrictions improves recovery in chronic NA that fails conservative management: 9/11 operative vs 3/13 nonsurgical patients recovered clinically, with EMG-confirmed axonal regeneration (PMID: 32868098). Surgery is generally considered after ~6–12 months without recovery. Nerve resection/direct suture or grafting is used for unsalvageable segments (PMID: 41163648). Phrenic nerve reconstruction is an option for symptomatic diaphragmatic paralysis (PMID: 36031309). Tendon transfers when recovery does not occur after ~18 months. Early neurolysis/nerve grafts remain controversial (PMID: 38176820). NCIT:C15329 (Surgical Procedure), NCIT:C157810 (Neurolysis).

Rehabilitation. Modern multidisciplinary rehabilitation targeting motor relearning, energy conservation, and self-management of pain/fatigue — not strength training — improves functional outcomes. An RCT (n=47) showed an adjusted mean SRQ-DLV group difference of 8.60 (95% CI 0.26–16.94, p=0.044), with clinically relevant improvement in 59% (rehab) vs 33% (usual care), NNT = 4 (PMID: 36697215):

"The mean group difference adjusted for sex, age and SRQ-DLV baseline score was 8.60 (95%CI: 0.26 to 16.94, p=0.044)"

The recommended strategy explicitly avoids strength training (PMID: 39402917):

"target compensatory abnormal motor control and fatigue by focusing on motor coordination, energy conservation strategies, and behavioral change, rather than strength training which may worsen the symptoms"

Multimodal programs (physiotherapy, scapular stabilization) show benefit in case reports (PMID: 40213747). NCIT:C15296 (Physical Therapy), NCIT:C15315 (Rehabilitation Therapy).

Not established for NA (not applicable at present): pharmacogenomics, gene therapy, RNA-based therapy, cell therapy, targeted molecular immunotherapy.

13. Prevention

Primary prevention. No population-level primary prevention exists for sporadic NA. Trigger awareness/avoidance and, in HNA, avoidance of provocations before elective surgery may help.

Secondary prevention / early detection. Early clinical recognition plus imaging (US/MRN) enables timely corticosteroids within the critical first-month window, which improves outcomes (PMID: 19321467). Increased awareness in orthopedic and primary-care settings is emphasized to prevent misdiagnosis (PMID: 34435146).

Tertiary prevention. Rehabilitation to prevent chronic scapular dyskinesia, contractures, and disability; energy-conservation strategies to manage fatigue; prophylactic steroids/IVIG to reduce peri-procedural or peripartum attacks in HNA (PMID: 38176820).

Genetic counseling. Appropriate for HNA families — autosomal dominant inheritance, ~50% offspring risk, variable expressivity; SEPT9 testing informs family planning and pre-procedure prophylaxis.

Immunization / public-health / environmental interventions. No vaccine prevents NA; conversely, certain vaccinations are recognized (rare) triggers. HEV exposure reduction (food safety, livestock-contact awareness) is a plausible environmental measure given HEV's trigger role.

14. Other Species / Natural Disease

A naturally occurring inflammatory brachial plexus neuritis exists in cats (Felis catus, NCBI:txid9685), providing a comparative-species analogue (PMID: 29925717):

"A postmortem examination revealed swollen radial nerves and cervical nerve roots in which infiltration of inflammatory cells was histologically confirmed"

This hypertrophic neuritis caused tetraparesis with histologically confirmed inflammatory infiltration, paralleling the human immune/inflammatory mechanism. Orthologous gene: Sept9/SEPTIN9 is conserved across mammals (human HGNC:7323; mouse Sept9). Comparative biology: conservation of septin cytoskeletal function and of immune-mediated peripheral neuritis supports cross-species mechanistic relevance. Zoonotic angle: HEV is zoonotic (swine reservoir), relevant to the trigger rather than to NA transmission; NA is not itself transmissible. Formal OMIA/veterinary registry entries were not established in the reviewed literature — a knowledge gap.

15. Model Organisms

No dedicated animal model that recapitulates the full NA phenotype was identified in the reviewed literature. Relevant systems include:

  • In vitro / molecular models: Molecular-dynamics simulation of mutant septin-9 demonstrates impaired microtubule binding/bundling (PMID: 39428775); cell-based assays of septin–microtubule association define the isoform-1 MAP-like motif and show HNA mutations abrogate it (PMID: 34854883). Evidence type: computational and in vitro.
  • Naturally occurring animal analogue: feline hypertrophic brachial plexus neuritis (spontaneous, not engineered) (PMID: 29925717).
  • Genetic models (knockout/knock-in/transgenic Sept9): not established for the NA phenotype in the reviewed literature.

Limitations of available models: they capture the molecular (septin/microtubule) dimension or the inflammatory-pathology dimension separately, but no single model reproduces the triad (genetic predisposition + mechanical vulnerability + immune trigger) with hourglass-constriction formation. Recommended resources for future work: MGI (mouse Sept9), IMPC/KOMP, Cellosaurus/ATCC and patient-derived iPSC-neuron models.

Mechanistic Model / Interpretation

NA is best understood as a "three-hit" focal inflammatory neuropathy. The first hit is a predisposing background — a SEPT9 mutation compromising microtubule-based cytoskeletal regulation in HNA, or an undefined susceptibility in INA. The second hit is a mechanical/anatomical vulnerability of specific plexus segments, possibly through a leaky epineurial blood–nerve barrier that grants immune cells access. The third hit is an immune trigger — most compellingly an infection such as HEV, but also vaccination, surgery, childbirth, or exertion — that ignites a multifocal mononuclear inflammatory attack. The convergence produces the disease's structural signature, the hourglass constriction/nerve torsion, and drives the stereotyped clinical sequence of severe pain → patchy paresis/atrophy/sensory loss → slow, often incomplete recovery.

This model unifies otherwise disparate observations: why NA recurs and starts earlier in SEPT9 carriers (stronger first hit); why bilateral and phrenic disease cluster with viral infection/HEV (a systemic third hit reaching multiple vulnerable segments); why nerve biopsies show inflammation (the effector mechanism); and why steroids help acutely (dampening the immune hit) but weakness responds mainly to time, rehabilitation, and — for fixed constrictions — surgery (repairing the structural end-lesion). The directionality is clear: genetic/mechanical predisposition is upstream and permissive; the immune trigger is the proximate initiator; hourglass constriction and axonal loss are the downstream lesions producing symptoms; chronic scapular dyskinesia is the tertiary consequence of incomplete regeneration and maladaptive motor control.

Evidence Base

PMID Contribution Supports finding
16371410 246-case clinical spectrum; three-phase pain; INA vs HNA F001
21556032 SEPT9 in 55% of HNA families; triad pathophysiology F002, F003
34854883 Septin-9 isoform-1 MAP motif; HNA mutations abrogate MT binding F002
39428775 MD simulation: mutation impairs MT binding/bundling F002
30019529 Childhood HNA, exon-2 duplication, platelet dysfunction F002
36214185 Acute-phase US/MRN; HGCs 74%, muscle edema 91% F003, F008
33823638 Incidence ~1/1000/yr; Gd-MRI/MRN confirmatory F004, F008
38835178 Poor prognosis (25% unable to work at 3 yr); steroids first F004
19321467 Prednisolone shortens pain (12.5 vs 20.5 d) F004
39364568 Infectious trigger 26.3%; viral infection → bilateral (p=0.003) F005
40534221 HEV NA with bilateral phrenic/diaphragm paralysis F005
38657646 HEV → phrenic/diaphragmatic dysfunction F005
36697215 >60% residual; rehab RCT (Δ8.60, p=0.044) F006, F011
39402917 Motor-relearning strategy, not strength training F006
8614534 Nerve biopsy: multifocal mononuclear infiltrates F007
29925717 Feline inflammatory brachial plexus neuritis analogue F007
32140911 Diagnosis is clinical F008
32868098 Microneurolysis of HGCs (9/11 vs 3/13 recover) Treatment
38543940 Systematic review: PTS after COVID-19 vaccines Etiology
19588414 Cochrane: no RCTs; steroid open-label evidence Treatment

Challenges / caveats in the evidence base. The prednisolone and rehabilitation data come from observational studies and a single small RCT (n=47), respectively; the Cochrane review found no RCTs of drug therapy. HGC prevalence figures derive from modest imaging series. These limit the strength of causal treatment claims.

Limitations and Knowledge Gaps

  1. No high-level RCT evidence for pharmacotherapy — corticosteroid benefit rests on observational data (PMID: 19588414; PMID: 19321467).
  2. Molecular profiling absent — no NA-specific transcriptomic, proteomic, metabolomic, single-cell, or CRISPR/RNAi data were identified; the immune effector cells and antigens remain undefined.
  3. INA genetics undefined — the "genetic predisposition" in idiopathic NA is inferred, not mapped; no GWAS/susceptibility loci established.
  4. Modifier genes, epigenetics, penetrance/expressivity metrics, carrier frequency for SEPT9-HNA are not quantified.
  5. Mechanism of hourglass constriction — the link from inflammation to focal constriction/torsion is described but not mechanistically demonstrated.
  6. No engineered animal model recapitulating the full triad; the feline analogue is naturally occurring and incompletely characterized.
  7. Identifier confirmation — MONDO/OMIM/Orphanet/ICD codes should be verified against current ontology releases before database ingestion.

Proposed Follow-up Experiments / Actions

  1. Randomized controlled trial of early corticosteroids ± IVIG in acute NA, powered for functional recovery and pain outcomes, to convert observational signals into Level-I evidence.
  2. Multi-omic characterization of NA nerve/biopsy and blood (bulk + single-cell RNA-seq, proteomics) during acute attacks to identify immune effector populations, candidate autoantigens, and biomarkers — populating the currently empty molecular-profiling domain.
  3. SEPT9 genotype–phenotype and penetrance study across HNA registries, including CNV analysis, to quantify penetrance, expressivity, and modifier loci; establish carrier frequency in gnomAD-linked cohorts.
  4. Prospective HEV-screening protocol in all new NA cases (IgM/IgG + RNA + transaminases), especially with phrenic/bilateral involvement, to define the treatable-trigger fraction and guide etiologic management.
  5. Engineered Sept9 knock-in mouse (e.g., R106W) with an inducible immune/inflammatory challenge to test the three-hit model and reproduce hourglass-constriction formation.
  6. Standardized imaging staging (US/MRN) with defined timing to predict which HGCs spontaneously resolve versus require early neurolysis, refining the 6–12-month surgical decision window.
  7. Ontology reconciliation — verify and finalize MONDO, OMIM, Orphanet, ICD-10/11, MeSH, HPO, GO, CL, and UBERON term assignments for knowledge-base ingestion.

Report compiled from 8 confirmed findings and 47 reviewed papers across a 5-iteration autonomous investigation. Evidence types span human clinical cohorts, case-control and observational studies, one small RCT, nerve-biopsy histopathology, in vitro/computational molecular studies, and a naturally occurring veterinary analogue.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 40
Resolved 40
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 40
On topic 16
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:40213747 (3 mentions) - Functional Restoring in Parsonage-Turner Syndrome With a Multimodal Rehabilitation Program: A Case Report.
  • shared terms: pain

Weighed against this report's own most characteristic terms: hna, sept9, nerve, attack, trigger, pain, plexus, hev, genetic, phrenic, brachial, immune, involvement, ina, clinical, acute, mutation, chronic, multifocal, infection.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 35
Resolved 32
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2
Terms whose name was checked 23
Terms named correctly 14
Terms named as a different term 8
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0100053 (1 mention) - the report calls it "neuralgic amyotrophy"; MONDO calls it anaphylaxis
  • UBERON:0001824 (1 mention) - the report calls it "brachial plexus"; UBERON calls it mucosa of larynx
  • UBERON:0001379 (1 mention) - the report calls it "deltoid"; UBERON calls it vastus lateralis
  • NCIT:C198 (1 mention) - the report calls it "Prednisone"; NCIT calls it Acetaminophen
  • NCIT:C1409 (1 mention) - the report calls it "Corticosteroid"; NCIT calls it Carbenicillin Indanyl Sodium
  • NCIT:C579 (1 mention) - the report calls it "Immunoglobulin therapy"; NCIT calls it Inorganic Chemical
  • NCIT:C157810 (1 mention) - the report calls it "Neurolysis"; NCIT calls it Cervical Cancer Surgery
  • NCIT:C15296 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Isolated Chemotherapeutic Perfusion

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • UBERON:0003732 (1 mention), reported as "phrenic nerve" - UBERON does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0005874 (1 mention) - the report calls it "microtubule cytoskeleton"; GO calls it microtubule

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.