Raeder paratrigeminal syndrome (ie, paratrigeminal neuralgia) is characterized by severe, unilateral facial pain and headache in the distribution of the ophthalmic division of the trigeminal nerve in combination with ipsilateral oculosympathetic palsy or Horner syndrome. (See Etiology and Pathophysiology and Presentation.)
The first patient described by Raeder, in 1918, had an incomplete Horner syndrome with preserved sweating on the side of the lesion. Raeder originally described absent facial anhidrosis in the paratrigeminal syndrome, although the literature suggests no definite consensus concerning the facial sweating pattern.
Subtypes (Boniuk and Schlezinger)
In 1962, Boniuk and Schlezinger described 2 subtypes of Raeder paratrigeminal syndrome.[1] Group I included patients with neuralgia, oculosympathetic paralysis, and parasellar nerve involvement. The responsible lesions were believed to be localized to the middle cranial fossa, requiring an extensive workup (eg, local or metastatic tumors).
In group II patients, the condition occurred without parasellar involvement but was associated with oculosympathetic paralysis and neuralgia. These cases were felt to be more benign than those of group I.
Some causative conditions in group II included migraine, cluster headache, hypertension, trauma, inflammatory disease, sinusitis, syphilitic osteitis, herpes zoster, otitis, and pneumonitis.
Subcranial aneurysms also have been described as a cause in either subtype.[2] A rare cause includes carotid dissection and should be considered early in the differential diagnosis of Raeder syndrome.[3]
Subtypes (Grimson and Thompson)
Grimson and Thompson described 3 major groups in 1980.[4] While those in group I were felt to require an extensive evaluation, those in the 2 latter groups were felt to have a more benign prognosis. However, obtain a thorough evaluation as indicated, regardless of the subtype, the 3 of which are characterized as follows (see Etiology and Pathophysiology and Presentation):
Group I - Includes patients with multiple parasellar cranial involvement or involvement of any or all divisions of the trigeminal nerve
Group II - Includes patients with cluster headache with an isolated oculosympathetic paresis
Group III - Includes patients with pain atypical for cluster headache, with involvement of the ophthalmic division of the trigeminal nerve
An additional variant
In 1978, 6 patients were described and 31 similar patients reviewed whose symptoms were consistent with a pericarotid syndrome.[5] These patients' conditions were characterized by oculosympathetic paralysis, ipsilateral head pain, and anhidrosis with otherwise intact facial sweating.
In these cases, the site of the lesion of the oculosympathetic fibers was believed to be pericarotid rather than paratrigeminal in distribution.
The syndrome thus was renamed in the absence of intracranial disease. These patients constitute a unique clinical group with findings similar to Raeder syndrome that can be localized to an area in and around the internal carotid artery and affected by diverse pathologic processes.
Raeder felt that the syndrome was due to a limited space-occupying lesion in the paratrigeminal area of the middle cranial fossa.
Benign forms of Raeder syndrome without paratrigeminal cranial nerve involvement have also been reported.[6] One such case later evolved into an indomethacin-responsive hemicranial headache that fulfilled the diagnostic criteria for hemicrania continua.[7]
The pathophysiologic site of the painful oculosympathetic palsy involves the location at which oculosympathetic fibers exit the internal carotid artery to join the ophthalmic division of the trigeminal nerve. Various combinations of cranial deficiencies (nerves II-VI) also may be involved.
According to Goadsby, paratrigeminal oculosympathetic syndrome may be a more accurate name than Raeder paratrigeminal syndrome, because an analysis of the anatomy of the oculosympathetic innervation may place the lesion best in the middle cranial fossa, medial to the trigeminal ganglion.[8]
Raeder syndrome localizes to lesions of the middle cranial fossa involving oculopupillary sympathetic fibers originating from the internal carotid artery plexus and traveling with the trigeminal and oculomotor nerves.[9] Therefore, careful imaging of this area is highly recommended.
Sweating is preserved in Raeder paratrigeminal syndrome, in contrast to Horner syndrome, since some third-order sympathetic fibers are spared (see the image below). These particular fibers travel with the external carotid artery and its branches and are involved in the production of facial sweating. The clinical localization is therefore distal to the carotid bifurcation. If additional parasellar cranial nerves are involved, the lesion may localize more specifically to the middle cranial fossa.[10]
View Image
Cervical sympathetic pathway, including oculosympathetic fibers. A lesion at A would produce a complete Horner syndrome with ipsilateral loss of facia....
Associated morbidities
Raeder syndrome has been associated with several conditions, including the following:
Symptomatic resolution in Raeder paratrigeminal syndrome usually occurs within an interval of 2-3 months. If pain persists or if atypical features are noted, investigate and manage secondary causes.
Morbidity and mortality
As previously mentioned, Raeder syndrome has been associated with several conditions, including head trauma, hypertension, vasculitis, migraine headaches, parasellar mass lesions, and internal carotid artery dissection or aneurysm.[12] Therefore, the morbidity and mortality depend on the underlying etiology, and the diagnosis of the condition warrants a full evaluation to identify an underlying cause.
Raeder paratrigeminal neuralgia is a rare syndrome. The exact incidence of this disorder in the United States is unknown.[10] It is less common than Horner syndrome.
Raeder paratrigeminal syndrome seems to occur almost exclusively in males. Case reports vary as to the age of onset or diagnosis. The original case reports from Raeder involved patients aged 18–65 years. However, onset appears most prevalent in middle or old age.
A case report in Headache detailed a 27-year-old man presenting with headache, blurred vision, and dizziness that was attributed to lyme disease.[13] The patient was treated with antibiotics with improvement of symptoms. This case illustrates that lyme disease should be considered in patients who may present with Raeder's when no other cause is found.
Raeder syndrome can also present with other disease states in the head or neck region. A case of bacterial sinusitis has been reported in the literature,[14] and while less common, it should be considered in the differential diagnosis.
A case of carotid artery invasion by a malignancy of unknown primary was described in a patient presenting with unilateral headache and incomplete Horner's syndrome in the absence of anhidrosis.[15] Compressive lymphadenopathy affecting the carotid system and creating sympathetic dysfunction was felt to be the underlying mechanism.
Another report details the case of a 52-year-old woman presenting with V1 distribution pain and ptosis and photobia of the left eye. Multiple cranial neuropathies including 2, 3, 5, and 6 were seen and the headache became chronic with exacerbations of autonomic symptoms and a subsequent diagnosis of hemicrania continua was made. This case illustrates a rare presentation of Raeder syndrome evolving into hemicrania continua, treated with oral prednisone and onabotulinumtoxin A.[16]
History for Raeder paratrigeminal syndrome suggests trigeminal nerve involvement with pain, sensory or motor deficits, and/or ipsilateral oculosympathetic paresis. It resembles Horner syndrome and manifests as oculosympathetic paresis with ptosis and miosis. (See the image below.)
View Image
Evident in this patient are the mild ptosis of the left upper eyelid, the slight elevation of the left lower eyelid, and the miosis of the left eye. R....
Unlike Horner syndrome, facial sweating and ipsilateral trigeminal sensory irritation are preserved, leading to production of facial pain.[10] Other parasellar cranial nerves also may be involved and an enophthalmos also may be apparent.[17]
The pain associated with Raeder syndrome is deep and boring and is localized in or around the eye. Intermittent, lancinating pain also may occur. Typically self-limited, the pain usually remits in 2-3 months.[17]
The pain occasionally follows a recurrent pattern. It can be associated with conjunctival tearing, erythema, enophthalmos, and decreased intraocular pressure. The pain is less well defined than the pain of trigeminal neuralgia.
Because painful Horner syndrome can occur with other diseases, such as cluster headache and carotid dissection or aneurysm, a diagnosis of Raeder paratrigeminal syndrome should be made on clinical and radiologic grounds.[9]
In the paratrigeminal syndrome described by Raeder, unilateral oculosympathetic paresis and evidence of trigeminal nerve involvement are the 2 hallmark features on clinical examination.[18]
Because some third-order sympathetic fibers are spared in Raeder paratrigeminal syndrome, sweating is preserved in this disorder, in contrast to Horner syndrome.
Ophthalmologic Manifestations of Atopic Dermatitis
sinusitis
Vascular Surgery for Arteriovenous Malformations
Approach Considerations
As previously stated, because painful Horner syndrome can occur with other diseases, such as cluster headache and carotid dissection or aneurysm, a diagnosis of Raeder paratrigeminal syndrome should be made on clinical and radiologic grounds.[9]
While most cases of Raeder paratrigeminal syndrome are benign, a thorough evaluation to exclude secondary causes may be warranted, particularly if parasellar nerve involvement is evident.
Basic laboratory analysis to evaluate for inflammatory or infectious etiologies also may be warranted.
A basic chemistry profile, a complete blood count (CBC), the erythrocyte sedimentation rate, antinuclear antibody, and rheumatoid factor may be helpful in screening for inflammatory or infectious causes.
The neurodiagnostic evaluation should include magnetic resonance imaging (MRI) and MR angiography (MRA) of the brain. These studies help to exclude secondary causes such as dissection, vascular anomaly, and aneurysm.
Cerebral arteriography may be considered if clinically indicated or if MRA findings warrant further evaluation.
Unless intracranial pathology exists, treatment of Raeder paratrigeminal syndrome remains predominantly symptomatic. Avoidance of vasodilators and alcohol is recommended due to the potential for exacerbation of pain.
When parasellar involvement is absent, steroids (either oral or intravenous) may be beneficial. Nolph and Dion also have suggested analgesics, ergotamines, and vitamin B therapy.[17]
Surgical treatment
Surgery is not indicated for most patients unless a secondary cause is found that justifies surgical intervention.
For the management of pain associated with Raeder paratrigeminal syndrome, the antispasticity medication baclofen or anticonvulsants such as gabapentin, pregabalin, carbamazepine, and topiramate may be effective. Anti-inflammatory agents can also be effective, and, at times, narcotic analgesics may be necessary.
The efficacy of tricyclic antidepressants (TCAs) has been demonstrated in controlled trials for idiopathic facial pain and appears to be independent of the antidepressant effect. Steroids may also be effective in some patients.
Clinical Context:
Topiramate is indicated for migraine headache prophylaxis and for use as an anticonvulsant. Its precise mechanism of action is unknown, but the following properties may contribute to its efficacy:
• Blocks voltage-dependent sodium channels - According to electrophysiologic and biochemical evidence
• Augments the activity of the neurotransmitter GABA at some GABA-A receptor subtypes
• Antagonizes the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate subtype of the glutamate receptor
• Inhibits the carbonic anhydrase enzyme - Particularly isozymes II and IV
Clinical Context:
Gabapentin is effective in treating neuralgia and chronic pain, likely due to its immunomodulatory effect. Gabapentin is structurally related to gamma-aminobutyric acid (GABA) but does not interact with GABA receptors. It is not converted metabolically into GABA or a GABA agonist and is not an inhibitor of GABA uptake or degradation. Gabapentin does not exhibit an affinity for other common receptor sites.
Clinical Context:
Carbamazepine is the drug of choice that may reduce polysynaptic responses and block posttetanic potentiation. This agent may depress the activity of the nucleus ventralis of the thalamus or decrease synaptic transmission or summation of temporal stimulation, leading to neural discharge by limiting the influx of sodium ions across the cell membrane or other unknown mechanisms. The target blood serum concentration is 4-12mg/L.
Clinical Context:
Pregabalin is similar to gabapentin but has a faster clinical effect without the slow titration. It reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function. Twice-daily dosing may improve compliance.
Clinical Context:
Naproxen is well-absorbed orally and is not usually associated with rebound headaches. It is used for the relief of mild to moderate pain. Naproxen inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. It is inexpensive and can be purchased over the counter.
Clinical Context:
Indomethacin is thought to be the most effective NSAID for the treatment of pain, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.
Clinical Context:
Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.
Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial to patients who have sustained trauma or injuries.
Clinical Context:
Corticosteroids are the most commonly used and most versatile immunosuppressants. Corticosteroids have many complex actions and a broad range of immunosuppressive and anti-inflammatory effects. They induce lymphocytopenia, interfere with the production and function of numerous lymphokines, and disrupt intercellular communication among leukocytes. Use the lowest effective dose, weighing benefits against risks in each patient.
Clinical Context:
Methylprednisolone is available in intravenous (IV)/intramuscular (IM) or oral (PO) form. Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity.
Clinical Context:
Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear (PMN) leukocyte activity. It is a commonly used oral agent.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.
Clinical Context:
Amitriptyline can be used with a slow titration schedule. This agent can be useful if a mild sedative effect is desired. It can be dosed at night.
Clinical Context:
Clomipramine is a dibenzazepine compound belonging to the family of tricyclic antidepressants. The drug inhibits the membrane pump mechanism responsible for the uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons.
Clomipramine affects serotonin uptake while it affects norepinephrine uptake when converted into its metabolite desmethylclomipramine. It is believed that these actions are responsible for its antidepressant activity.
Clinical Context:
Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by the presynaptic neuronal membrane. It inhibits histamine and acetylcholine activity and has proven useful in the treatment of various forms of depression associated with chronic pain.
Clinical Context:
This is the original TCA used for depression and has been shown to help treat chronic pain. These agents have been suggested to act by inhibiting reuptake of noradrenaline at synapses in central descending pain-modulating pathways located in the brainstem and spinal cord.
These are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. TCAs have central effects on pain transmission. They block the active reuptake of norepinephrine and serotonin.
Clinical Context:
Baclofen is a centrally acting muscle relaxant; its precise mechanism of action is unknown. It is a GABA analog and may exert its effects by stimulation of GABA-beta receptors. Baclofen inhibits monosynaptic and polysynaptic reflexes at the spinal level by hyperpolarization of afferent terminals.
Clinical Context:
Cyclobenzaprine acts centrally and reduces motor activity of tonic somatic origins, influencing alpha and gamma motor neurons. It is structurally related to the tricyclic antidepressants.
Skeletal muscle relaxants have modest, short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. Long-term improvement over placebo has not been established.
Cyclobenzaprine often produces a "hangover" effect, which can be minimized by taking the nighttime dose 2-3 hours before going to sleep.
Clinical Context:
Carisoprodol is a short-acting medication that may have depressant effects at the spinal cord level.
Skeletal muscle relaxants have modest short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. Long-term improvement over placebo has not been established.
Clinical Context:
Tizanidine is a centrally acting muscle relaxant that is metabolized in the liver and excreted in the urine and feces. It is used in patients with predominantly upper motor neuron involvement. It is not a DEA-controlled substance.
What is Raeder paratrigeminal syndrome?What are the subtypes of Raeder paratrigeminal syndrome described by Boniuk and Schlezinger?What are the subtypes of Raeder paratrigeminal syndrome described by Grimson and Thompson?What is a variant of Raeder paratrigeminal syndrome?What causes Raeder paratrigeminal syndrome?Which conditions are associated with Raeder paratrigeminal syndrome?What is the prognosis of Raeder paratrigeminal syndrome?What is the morbidity and mortality of Raeder paratrigeminal syndrome?What is the prevalence of Raeder paratrigeminal syndrome?What are case reports of Raeder paratrigeminal syndrome?Which clinical history findings are characteristic of Raeder paratrigeminal syndrome?Which physical findings are characteristic of Raeder paratrigeminal syndrome?Which conditions are included in the differential diagnoses of Raeder paratrigeminal syndrome?What are the differential diagnoses for Raeder Paratrigeminal Syndrome?How is Raeder paratrigeminal syndrome diagnosed?What is the role of lab testing in the workup of Raeder paratrigeminal syndrome?What is the role of imaging studies in the workup of Raeder paratrigeminal syndrome?How is Raeder paratrigeminal syndrome treated?What is the role of surgery in the treatment of Raeder paratrigeminal syndrome?What is the role of medications in the treatment of Raeder paratrigeminal syndrome?Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Raeder Paratrigeminal Syndrome?Which medications in the drug class Antidepressants, TCAs are used in the treatment of Raeder Paratrigeminal Syndrome?Which medications in the drug class Corticosteroids are used in the treatment of Raeder Paratrigeminal Syndrome?Which medications in the drug class Analgesics, Other are used in the treatment of Raeder Paratrigeminal Syndrome?Which medications in the drug class Anticonvulsants, Other are used in the treatment of Raeder Paratrigeminal Syndrome?
Steven H Schechter, MD, Clinical Assistant Professor, Department of Neurology, Wayne State University School of Medicine; Consulting Staff, Division of Neurology, William Beaumont Hospital
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly, US World Meds, Sanofi Genzyme.
Chief Editor
Robert A Egan, MD, NW Neuro-Ophthalmology
Disclosure: Received honoraria from Biogen Idec and Genentech for participation on Advisory Boards.
Acknowledgements
Jorge E Mendizabal, MD Consulting Staff, Corpus Christi Neurology
Jorge E Mendizabal, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, National Stroke Association, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Epifanov, Y, Back, T. Oculosympathetic Paratrigeminal Paralysis With Isolated V@ Involvement in Carotid Artery Dissection. Arch Neurol. march/2007. 64:448-449.
Murphy, MM, Szabados, EM, Mitty, JA. Lyme disease Associated with Postganglionic Horner Syndrome and Raeder Paratrigeminal Neuralgia. J Neuro-Ophthalmol. 2007. 27:123-124.
Cervical sympathetic pathway, including oculosympathetic fibers. A lesion at A would produce a complete Horner syndrome with ipsilateral loss of facial sweating; a lesion at B would produce oculosympathetic paresis, but with preserved facial sweating. Reprinted with permission (Hanley and Belfus, Inc. Academic Emergency Medicine 1996; 3(9); 864-867.)
Evident in this patient are the mild ptosis of the left upper eyelid, the slight elevation of the left lower eyelid, and the miosis of the left eye. Reprinted with permission (Copyright American Society of Contemporary Ophthalmology. Annals of Ophthalmology 1978; 10(9); 1181-1187.)
Cervical sympathetic pathway, including oculosympathetic fibers. A lesion at A would produce a complete Horner syndrome with ipsilateral loss of facial sweating; a lesion at B would produce oculosympathetic paresis, but with preserved facial sweating. Reprinted with permission (Hanley and Belfus, Inc. Academic Emergency Medicine 1996; 3(9); 864-867.)
Evident in this patient are the mild ptosis of the left upper eyelid, the slight elevation of the left lower eyelid, and the miosis of the left eye. Reprinted with permission (Copyright American Society of Contemporary Ophthalmology. Annals of Ophthalmology 1978; 10(9); 1181-1187.)
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