Abstract
Neuralgic amyotrophy, also known as Parsonage and Turner syndrome, is a painful nerve disorder that can present with a variety of clinical manifestations. The exact cause is unknown, but autoimmune, genetic, infectious, environmental, and biomechanical processes have been implicated. Neuralgic amyotrophy is a challenging neurologic condition to diagnose and treat. It usually affects portions of the brachial plexus, most commonly the suprascapular and long thoracic nerves, but it can also involve the cervical or lumbosacral plexus, particularly in hereditary neuralgic amyotrophy, where recurrence rates are higher. Treatment is usually conservative, with support for the early use of corticosteroids, and most cases lead to a favorable outcome.
Keywords
Brachial plexopathy, Neuralgic amyotrophy, Neuropathy, Parsonage and Turner syndrome, Plexopathy
Introduction
Neuralgic amyotrophy, also known as Parsonage and Turner syndrome, is a painful nerve disorder related to a lesion that is severe enough to cause muscle atrophy. It usually presents with acute pain, most commonly affecting the brachial plexus. It is a syndrome that can present with a variety of clinical manifestations. The exact cause is unknown, but autoimmune, genetic, infectious, environmental, and biomechanical processes have been implicated.
Incidence
Neuralgic amyotrophy is a clinical diagnosis. At this time, a definitive diagnosis cannot be made based solely on serologic markers, imaging, or electromyography (EMG), without including the clinical history and physical examination.
Defining a true incidence is therefore difficult, because multiple overlapping clinical definitions and criteria exist when defining the disorder. The clinical picture overlaps with other more common shoulder and neck pathologies and can be overlooked without directed training. The typical syndrome of sudden severe unilateral shoulder pain followed by scapular winging or decreased pinch grip occurs in approximately 70% of cases.
The annual incidence has been described as approximately 2–3/100,000 people in two populations, one in Rochester, Minnesota, and the other in the United Kingdom. Following training on how to diagnose neuralgic amyotrophy, the approximate annual incidence increased to 1/1000 people in a population of approximately 14,000 primary care patients in the Netherlands.
However, these incidence studies have been performed primarily in small homogenous populations, and a true worldwide annual incidence is unknown.
The conservative incidence of 2–3/100,000 is comparable with that of Guillain-Barré syndrome (estimated 1–2/100,000) and multiple sclerosis in similar European populations (estimated 1/100,000 to 10/100,000). The condition is more common in men than in women (ratio of 2:1 or 3:2).
It is typically asymmetric, involving either exclusively one arm or affecting one side more than the other side. Studies vary and have shown either no statistical preference for sidedness or up to a 2:1 ratio favoring the right arm over the left.
Neuralgic amyotrophy has been described in the literature in ages from pediatric patients of less than 3 years old to the elderly, with a median age of 40 years and a normal distribution.
Etiology
Neuralgic amyotrophy is not a uniform disorder but a syndrome occurring secondary to a variety of precipitating factors and genetic phenotypes ( Table 23.1 ).
| Hereditary NA | Idiopathic | Hepatitis-E Associated | |
|---|---|---|---|
| Median age of onset | 20s (Van Alfen 2005) | 40s | Middle age (Dartevel) |
| Sex preference | No | Female:male 2:3 | Male |
| Sidedness | Variable | Unilateral | Bilateral |
| Involvement outside of brachial plexus | Phrenic, recurrent laryngeal, lumbosacral | Not typical | Phrenic nerve |
| Recurrence | 74% | 26% | |
| Dysmorphic features in patient and family | Yes | No | No |
The etiology of the disorder can be grossly divided into hereditary, and idiopathic or immune mediated. The hereditary form is more commonly recurrent (up to 74%), whereas the immune-mediated and idiopathic forms primarily occur in a sporadic or epidemic fashion as a one-time event with a minimal recurrence rate. The highest recurrence rate in idiopathic neuralgic amyotrophy reported in the literature was described in a selected series of patients with a 26% recurrence rate.
The condition was first described by Dyke in 1916, in a case report of a peripheral nerve lesion after a patient received antitetanic serum, followed in 1941 by 42 cases of “brachial plexus neuritis” by Wyburn-Mason and 46 cases of “localised neuritis of the shoulder girdle” in 1943 by Spillane. In 1948, Parsonage and Turner reported 136 cases of “neuralgic amyotrophy.”
The original case series primarily described adult patients who presented with an acute attack after various precipitating factors such as infections, immunizations, and surgery or trauma. Most commonly, patients suffered a one-time event, with gradual improvement. In a minority of cases, patients suffered recurrent attacks on the uninvolved side weeks or months after the initial episode, often after minor precipitating events. Various triggering events have been described in the literature, including infections, immunization, surgery, trauma, exercise, pregnancy, parturition, psychological stress, and burns. Identification of triggering events was reported as 72% in the original series by Parsonage and Turner and 53% –73% in more recent studies. Cases with no pain but otherwise clinical findings of patchy weakness in the upper extremity have been described in 3.7%.
Hereditary Neuralgic Amyotrophy
A hereditary form has been described since 1960. The patients involved have varied expression of dysmorphic features, including hypotelorism, epicanthus, microstomia, dysmorphic ears, cleft uvula and palate, and partial syndactyly of fingers or toes. The typical facial dysmorphism has been likened to a Modigliani portrait. Genetic studies of affected families have found mutations in a septin 9 repeat motif, which binds and bundles microtubules, also termed SEPT9. The SEPT9 mutation is located on the 17q25 chromosome and is inherited in an autosomal dominant pattern.
The typical patient affected with the familial form presents with an acute episode of neuralgic amyotrophy earlier in life, in the second and third decade, and can have one lifetime episode to multiple recurrent attacks, resulting in significant shoulder weakness. The affected family members show variable expression of dysmorphic features as well as variable presentation of brachial palsies. Most family members have at least one episode. The hereditary form is a systemic disease, and although it more commonly occurs in the upper extremity, it can affect any peripheral nerve. Besides affecting the lumbosacral plexus, hereditary neuralgic amyotrophy frequently affects the phrenic nerve, recurrent laryngeal nerve, and an episode can present as respiratory distress or dysphagia and hoarseness. Histologic studies have confirmed pathology affecting the lumbosacral plexus.
It is unclear whether similar molecular mechanisms and genetic background are involved in immune-mediated and idiopathic neuralgic amyotrophy. A genetic abnormality at 17q25 has been identified in one case of idiopathic neuralgic amyotrophy as occasionally found in some families with hereditary neuralgic amyotrophy. As a single episode of amyotrophy in a patient with hereditary neuralgic amyotrophy is difficult to differentiate from a sporadic case, except on the basis of dysmorphic features or familiar involvement, the importance of this case is unclear. A case of two siblings without dysmorphic features developing neuralgic amyotrophy after Epstein-Barr infection has also been published without clear answer whether the predisposing factor was a genetic predisposition or the infection. However, no cases of SEPT9 mutation have been identified in sporadic cases of neuralgic amyotrophy, further supporting that the hereditary and sporadic forms represent different etiologies of a similar disorder.
Idiopathic Neuralgic Amyotrophy
Since Dyke first described the association between the disorder and tetanus serum administration, multiple immune-mediated triggers for the development of acute neuralgic amyotrophy have been identified, including various infections and vaccinations. Viral infections such hepatitis E, B19, varicella-zoster, and Epstein-Barr virus have all been implicated in cases of nonhereditary neuralgic amyotrophy.
Van Alfen first described 10 male patients with gross elevations of liver enzymes and severe bilateral brachial plexopathy with phrenic nerve involvement. In 1984 an Italian group described a case of neuralgic amyotrophy associated with non-A non-B hepatitis. Hepatitis E was formally discovered and sequenced in 1990 by Reyes et al., and as such, definitive viral and serologic analysis of the case was not possible in 1984. Although infection with hepatitis E is typically asymptomatic, the virus has also been implicated in other neurologic syndromes such as Guillain-Barré syndrome and meningoencephalitis.
In 2009, Fong first described a patient with neuralgic amyotrophy with a confirmed acute hepatitis E infection. Serologic analysis of a cohort of UK and Dutch patients with neuralgic amyotrophy showed that 10% of the patients had anti-hepatitis E virus IgM antibodies, with EMG studies demonstrating bilateral brachial plexus involvement in all patients with positive hepatitis E infection.
Although other infectious agents have been implicated in isolated case reports of neuralgic amyotrophy, there are increasing numbers of cases of confirmed hepatitis E virus infections in association with a subset syndrome of neuralgic amyotrophy. The typical case involves a middle-aged male with bilateral brachial plexus involvement with or without phrenic nerve involvement.
At this time, it is still unclear whether the association of neuralgic amyotrophy with infectious agents is a result of direct infection or postinfectious immune-mediated injury to the peripheral nerves. The predilection for nerves of the brachial plexus and phrenic nerve is also unclear. Furthermore, it is still unclear what percentage of sporadic-type neuralgic amyotrophy is associated with an infectious agent, as multiple predilecting events such as trauma, surgery, and psychological stress have all been associated with acute episodes of idiopathic neuralgic amyotrophy and almost half of acute cases do not have an identifiable trigger.
Although an inflammatory-immune mechanism for idiopathic neuralgic amyotrophy is hypothesized, no specific immunologic markers have yet been discovered. Immune complexes such as those found in Guillain-Barré syndrome or acute inflammatory demyelinating polyradiculoneuropathy have not been found in idiopathic neurogenic amyotrophy. Infiltration of the plexus with T cells, mononuclear cells, and B cells has been demonstrated histologically, although it remains unclear whether the inflammatory cells are responding to a pathogen or an autoimmune trigger. Increased antiganglioside antibodies have been found in about one-third of patients with neuralgic amyotrophy. However, they too appear to be nonspecific. Defining the underlying etiology further may help guide targeted treatment in the future.
Presentation
Neuralgic amyotrophy presents with a wide constellation of symptoms, including acute onset of unilateral severe neuropathic shoulder, neck, and/or arm pain. Pain may occur as small isolated episodes that occur for a few weeks and ultimately lead to a major episode that involves severe pain unrelieved by position or analgesics. The initial stage is continuous intractable shooting and stabbing pain that lasts approximately 4 weeks. Pain symptoms are followed by progressive multifocal neurologic deficits, including paresis and atrophy. First signs of paresis may be immediate, with paresis developing in 24 h, or may take up to 2 weeks or longer. On average, symptoms first appear in 13.6 days in males and 8 days in females.
Muscles that are normally affected include those innervated by the brachial plexus and most commonly include muscles innervated by the upper and middle trunk of the brachial plexus, including the suprascapular nerve and long thoracic nerve. However, muscles innervated by the cranial nerves, phrenic nerve, and lumbosacral plexus may also be affected. In addition to pain and muscle atrophy, sensory changes may be appreciated but may be patchy in distribution. Atrophy is another clinical presentation associated with neuralgic amyotrophy; it develops as early as 2 weeks and may take up to 5 weeks to develop.
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