A 29-year-old woman presented with headache, fever, right leg numbness, and dysphagia.
History of the present illness
The patient was in good health until February 2005, when she awoke with a painful, red right eye. There was no ocular discharge, but the eye was photophobic and hurt with and without movement of the globe. Floaters were present. The contralateral eye was asymptomatic. She was diagnosed with iritis and treated with prednisolone acetate eye drops. Her symptoms resolved within 2 weeks.
One month later, the patient had a recurrence of the same symptoms in the right eye. Over the next 20 months, she experienced multiple recurrences of right eye inflammation whenever her prednisolone acetate was stopped. Her eye condition was characterized as panuveitis and multifocal choroiditis (Figure 1). The left eye remained uninvolved.
Methotrexate (MTX) therapy was started in September 2006. The weekly dose was increased over 9 months to 25 mg, and she discontinued her eye drops in June 2007. In August 2007, 29 months after the onset of ocular symptoms, the patient developed paresthesias in her pelvic region and numbness of the entire right lower extremity. She detected the urge to urinate and defecate but had no sensation in her perineum during these acts. A noncontrast magnetic resonance imaging (MRI) study of the lumbar and upper sacral spine revealed no central canal stenosis or neuroforaminal impingement. By September 2007, spontaneous partial improvement in her right leg numbness had occurred, such that it persisted only distal to her mid-calf. However, she was unable to fan the toes on her right foot.
A few weeks later, the patient began to experience bouts of nausea, vertigo, headache, and fevers to 101°C. Within 2 weeks, she began to have difficulty swallowing with both solids and liquids. She was only able to eat popsicles and imbibe sips of liquid. Finally, a few weeks later, the patient noticed decreased hearing in her right ear and observed that the ear felt as if she “had just gotten off an airplane.”
These new symptoms prompted MRI studies of the brain and the entire spinal cord, which revealed bilateral, multifocal white matter abnormalities that were concerning for demyelination (Figure 2). In addition, there was a 5-mm intramedullary lesion within the dorsal aspect of the thoracic spinal cord at T5, which was also suspicious for demyelination. The patient was referred to the emergency department.
Past medical history
The patient had a history of lead poisoning as a child, but otherwise had been healthy in childhood and adolescence. She was gravida 1, para 1.
The patient's parents were alive and well at ages 50 years (father) and 47 years (mother). The patient had 3 brothers in their mid-20s, one of whom had “a problem with his platelets” as a child.
The patient was of Puerto Rican heritage. She was married, had an 8-year-old daughter, and worked as a radiology technician. She did not smoke, drank alcohol moderately, and had no history of illicit drug use.
Medications and allergies
She was receiving MTX 25 mg weekly, folic acid 1 mg daily, and an oral contraceptive. She had no medication allergies.
Review of systems
The patient denied fever, weight loss, and fatigue. She had no photosensitivity, no rash, and no arthritis, but had noted mild alopecia since starting MTX. She also reported occasional oral ulcers since starting that medication. Before starting MTX, she had experienced ulcers only approximately once a year. Those episodes had been characterized by single oral ulcers that resolved over a few days. She had no history of genital ulcers. She denied shortness of breath, chest pain, or venous thrombotic events. She denied focal motor weakness except for the inability to fan her toes on the right foot.
Her temperature was 99.4°C, the pulse rate was 92 beats/minute, and the respiratory rate was 12 breaths/minute. The hearing was diminished in the right ear to finger rub. She had no oral ulcers. There was no Raynaud's phenomenon and no rash, and inspection of her nailbed capillaries was normal. She had no synovitis. The heart, lung, and abdominal examinations were normal. No genital lesions were present.
The neurologic examination was remarkable for the absence of meningismus. The patient did not exhibit any signs of cognitive dysfunction. She was fully alert, oriented, and lucid. Her visual acuity was 20/20 on the right and 20/30 on the left. The pupils were equally round and reactive to light and accommodation. There was no evidence of an afferent pupillary defect or color desaturation. The visual fields were full, and there was no ptosis. Extraocular movements, including saccades, were normal. Pain and temperature sensation were impaired on the left side of her face. Rinne and Weber tests suggested sensorineural hearing loss on the right side. Her tongue and palate movements were normal. Her motor examination was normal with the exception of symmetrically brisk deep tendon reflexes. The muscle tone was normal and both plantar responses were downgoing. The sensory examination was normal except for decreased temperature sensation in the left arm. Other sensory modalities were preserved. There was no evidence of ataxia and her gait and stance were normal. An examination by ophthalmology at this time revealed active iritis in the left eye.
The initial laboratory evaluation is shown in Table 1. A lumbar puncture revealed a cerebrospinal fluid (CSF) glucose level of 76 mg/dl (normal range 45–75) and a protein level of 46 mg/dl (normal range 5–55). Tube 1 had 343 red blood cells/mm3 and 68 white blood cells/mm3 (91% lymphocytes, 2% neutrophils, and 7% monocytes). Tube 4 had 8 red blood cells/mm3 and 61 white blood cells/mm3 (89% lymphocytes, 2% neutrophils, and 9% monocytes).
Table 1. Laboratory evaluation
White blood cell count, 1,000/μl
Differential count, %
Prothrombin time, seconds
International normalized ratio
Partial thromboplastin time, seconds
Urea nitrogen, mg/dl
Alkaline phosphatase, units/liter
Aspartate aminotransferase, units/liter
Alanine aminotransferase, units/liter
Lactate dehydrogenase, units/liter
Creatinine kinase, units/liter
Red blood cells/mm3
White blood cells/mm3
Serologic assays were performed (Table 1). A test for antinuclear antibodies by immunofluorescence was negative, as were assays for antibodies to double-stranded DNA and precipitins (Ro, La, Sm, and RNP) and a rapid plasma reagin test. The serum complement levels were normal. Assays for anticardiolipin antibodies, lupus anticoagulants, and neuromyelitis optica IgG were negative. A computed tomography scan of the chest showed no adenopathy or pulmonary parenchymal disease.
This 29-year-old woman has a history of right eye panuveitis and multifocal choroiditis that dates back more than 2 years. There is now iritis of the left eye. She also has neurologic symptoms and signs that include headache, dysphagia, decreased hearing in the right ear, sensory findings in her left face, weakness of the toes of her right foot, and bladder and bowel dysfunction. MRI reveals multifocal white matter hyperintensities, consistent with demyelination. Lumbar puncture reveals a lymphocytic pleocytosis, but oligoclonal bands are absent.
The evaluation to date permits us to exclude a number of multiorgan system disorders with neurologic involvement that could occur in a young woman. Specifically, the diagnoses of systemic lupus erythematosus and Sjögren's syndrome can be confidently eliminated by the negative serologic studies. Other rheumatic conditions such as polyarteritis nodosa and the antineutrophil cytoplasmic antibody–associated disorders are highly unlikely to cause such potentially devastating ocular and central nervous system (CNS) disease without involving other peripheral organs. Lyme disease can cause neurologic dysfunction through a variety of lesions but would not cause bilateral panuveitis.
The differential diagnosis centers around 4 conditions: a primary demyelinating disorder (either acute or chronic) of the CNS, sarcoidosis, Vogt-Koyanagi-Harada (VKH) syndrome, and Behçet's syndrome. Each of these entities is discussed in turn.
Acquired idiopathic demyelinating disorders in adults can be classified into 2 broad categories: acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). Differentiation between ADEM and MS may be difficult early in the disease course. Four points argue against a demyelinating syndrome in our patient. First, the patient's CSF pleocytosis was unusually prominent for either ADEM or MS, which almost never have more than 50 white blood cells/hpf. Second, oligoclonal bands, which suggest the intrathecal production of immunoglobulins, were not present. Third, although uveitis can be a feature of MS (pars planitis is the classic form of intraocular inflammation in MS), it would be exceptional for uveitis to have been the sole clinical disease manifestation nearly 2 years before the development of neurologic symptoms. Finally, hearing loss is distinctly uncommon in diseases such as ADEM or MS that are limited to the CNS, because the primary auditory cortex has bilateral innervation. When hearing loss occurs on an immunologic basis, the lesion is usually caused by involvement of the vestibulocochlear nerve (i.e., a peripheral nerve lesion).
Sarcoidosis can cause the patient's underlying ocular disorder and could also cause her CNS dysfunction. Sarcoidosis is rarely confined to the nervous system, but any neurologic features that do occur tend to develop early in the course of the disease, usually in the context of obvious concurrent systemic sarcoidosis. Cranial neuropathies are the most common neurologic presentation of sarcoidosis (occurring in 75%), but seizures, chronic meningitis, cognitive decline, movement disorders, and isolated mass lesions also occur in sarcoidosis. Facial palsy, the most common cranial neuropathy, is unilateral in 65% and bilateral in 35%. Uveoparotid fever, a syndrome peculiar to sarcoidosis, consists of facial neuropathy in the setting of uveitis, parotid gland enlargement, and fever, and is also known as Heerfordt's syndrome. This combination of clinical findings strongly suggests neurosarcoidosis. Optic neuropathy is the second most common cranial neuropathy but other cranial neuropathies, including vestibulocochlear neuropathy, have been reported.
Our patient's CSF findings are atypical for a demyelinating disorder but are consistent with neurosarcoidosis. Acute or chronic meningitis is detected in up to one-quarter of patients with neurosarcoidosis. The CSF analysis in such cases commonly shows a lymphocytic pleocytosis with elevated protein levels. Approximately one-fifth of patients have a low CSF glucose level.
Neurosarcoidosis has a predilection for the base of the brain. Therefore, involvement of the hypothalamic and pituitary gland is common. Periventricular white matter lesions that resemble MS are observed frequently on brain MRI scans. However, brainstem, cerebellar, and orbital mass lesions are less common. Finally, localized granulomatous mass lesions may affect any part of the CNS. These may be single or multiple and vary from small abnormalities to large tumors.
In this patient, the clinical picture is compatible with neurosarcoidosis. However, the absence of evidence of systemic granulomatous disease in the context of major involvement of the CNS would be quite unusual.
The VKH syndrome can be associated with meningeal irritation and occasionally with encephalopathy during the prodromal phase of the illness. More common features of this syndrome are vitiligo and uveitis. The incidence of VKH syndrome is increased among patients of Hispanic heritage, a point favoring that diagnosis in our patient. The neurologic signs and symptoms during the prodromal phase of VKH syndrome may be severe, including alteration of cognitive function, confusion, or psychosis. Seizures and coma rarely occur in the early stages, usually with more precipitous onset. However, significant focal neurologic disease is uncommon in VKH syndrome.
An asymptomatic CSF pleocytosis is more common than symptomatic meningitis in VKH syndrome. Eighty percent of patients with VKH syndrome who undergo lumbar puncture have a CSF pleocytosis (1–4). CSF cell counts range widely between 4 and 700 cells/mm3, but counts less than 100 cells/mm3 are seen in nearly 40%. CSF total protein level is often normal or only mildly elevated, and the glucose level is usually normal (2). The presence of melanin-laden macrophages in CSF can distinguish VKH syndrome from other conditions that can lead to a CSF pleocytosis, e.g., syphilis (5).
In our patient, the CSF pleocytosis is concordant with VKH syndrome, but the extensive imaging abnormalities and multiple focal neurologic signs are not.
Behçet's syndrome is a systemic vasculitis that has a predilection for affecting individuals with ancestry from along the Ancient Silk Route. Our patient, whose immediate forbears are from Puerto Rico, does not fit neatly into this category. However, both her ocular disease and her CNS manifestations are consistent with Behçet's syndrome. Patients with Behçet's syndrome can develop vision-threatening ocular manifestations in diverse parts of the eye and often have a panuveitis, indicating inflammation in both the anterior and posterior chambers as well as in the region of the pars plana (the so-called “intermediate uveitis”). Eighty-five percent of patients with Behçet's syndrome have bilateral eye disease (6), as our patient now does.
The neurologic manifestations of Behçet's syndrome can be categorized as parenchymal or non-parenchymal categories (7). Both relapsing–remitting disease courses and chronic, progressive patterns of disease have been described. The chronic, progressive pattern frequently leads to dementia, ataxia, and dysarthria. Neurologic manifestations usually occur in the context of active systemic disease and have been reported in up to nearly half of patients with Behçet's syndrome. However, some studies of neuro-Behçet's syndrome have inclusion bias because they focus on the neurologic aspects of the disease, leading to an enrichment of such cases. The percentage of patients with CNS disease is substantially smaller in most series, on the order of 15% (8). Isolated CNS disease is the presenting manifestation in only ∼6% of patients (8–12).
With regard to the parenchymal manifestations of CNS Behçet's syndrome, brainstem lesions are perhaps the most classic feature. The lesions of Behçet's syndrome have a predilection for the white matter, hence the tendency of this disease to mimic MS closely. The meningoencephalitis of Behçet's syndrome can be associated with acute confusion and isolated behavioral symptoms (psycho-Behçet's syndrome) (13). Rare cases with demyelinating or tumor-like lesions have been reported. Pure cerebellar or Parkinsonian syndromes, peripheral neuropathy (sometimes subclinical), and myelopathy are distinctly unusual.
Symptoms of non-parenchymal CNS Behçet's syndrome generally result from thrombotic complications of the cerebral sinuses. The usual site of thrombosis is the dural sinus, a complication that often leads to increased intracranial pressure. Parenchymal and non-parenchymal patterns of neurologic disease do not occur together in most patients. Their co-occurrence has been reported in up to 20% of patients in some series (7, 8, 14).
Behçet's syndrome is notoriously difficult to distinguish from MS on the basis of radiologic findings (15, 16). The usual radiologic approach to both diseases is MRI. Both Behçet's syndrome and MS can cause widespread CNS lesions with a predilection for the brainstem and white matter (9, 13, 17). The finding of brainstem atrophy in neuro-Behçet's syndrome has been proposed as a useful discriminator between these 2 conditions.
The CSF in our patient is quite characteristic of Behçet's syndrome. Patients with Behçet's syndrome often have a striking CSF pleocytosis (up to 400 × 106 cells/liter) (9, 10, 13, 17). The early stage is characterized by a neutrophilia, followed later by a lymphocytosis.
The major argument against Behçet's syndrome in our patient is that she has no history of mucocutaneous ulcerations (18, 19). This argument carries substantial weight, because between 97% and 99% of patients with Behçet's syndrome develop these lesions over time (20). Criteria issued in 1990 maintained that a patient could not be classified as having Behçet's syndrome in the absence of oral ulcers (19, 21). Many clinicians view aphthous oral ulcers as the sine qua non of Behçet's syndrome, but patients have been reported in whom oral ulcers do not occur (22). In a series from Istanbul of 880 consecutive patients, uveitis was the first symptom in 6% (11).
In addition to the absence of a clear history of oral ulcers, our patient also has no history of genital ulcers. These lesions, which are typically painful but occasionally asymptomatic, particularly in women, typically appear on the scrotum of male patients and on the labia of female patients (18). In addition, the patient has also had none of the other protean potential complications of Behçet's syndrome, particularly cutaneous disease, which can include erythema nodosum, a papulopustular rash, superficial thrombophlebitis, and the pathergy phenomenon (20).
The diagnosis of Behçet's syndrome was consistent with this patient's presentation, but the absence of both oral and genital ulcerations makes it difficult to be certain about that diagnosis.
HOSPITAL AND CLINIC COURSE
The initial diagnostic considerations focused on the suggestion from radiologic studies of demyelinating disease. Therefore, the patient was diagnosed tentatively as having either MS or ADEM. She was treated with daily methylprednisolone (1,000 mg) for 5 days. Her condition appeared to stabilize, and she was discharged to follow up in the neurology clinic for the initiation of therapy for MS.
Glucocorticoids are the standard initial approach to the treatment of MS in patients who present as ours did. In addition, for patients in whom the diagnosis of MS is clear cut, an immunomodulatory agent such as interferon-1α (IFN1α), IFN1β, and copolymer A is often added. These immunomodulatory agents have not been shown to be beneficial in sarcoidosis, the VKH syndrome, or Behçet's syndrome. (IFN2α, which is an effective agent in Behçet's syndrome , is a different compound functionally from the other IFN agents).
The cornerstone of sarcoidosis therapy remains glucocorticoids. Tumor necrosis factor (TNF) inhibitors such as infliximab or adalimumab are added to glucocorticoids in refractory cases. Etanercept, another TNF inhibitor, is not effective in sarcoidosis. The VKH syndrome usually responds acutely to systemic glucocorticoids with resolution of inflammation and subsequent glucocorticoid tapering. When patients develop chronic intraocular inflammation, steroid-sparing agents such as azathioprine, MTX, or mycophenolate mofetil are employed.
Until recently, conventional therapy for neuro-Behçet's syndrome consisted of lengthy courses of high-dose glucocorticoids and a cytotoxic agent such as cyclophosphamide or chlorambucil. Unfortunately, the long-term clinical outcomes of patients treated in this manner were often poor, and the treatment regimens themselves were associated with significant morbidity (18).
Because of the toxicities associated with conventional therapy for Behçet's syndrome, the Rheumatology Service favored treatment with a TNF inhibitor. There is a growing literature to support the early use of TNF inhibitors in patients with posterior uveitis or significant CNS disease (24, 25). Although TNF inhibition would have been a reasonable approach to the treatment of Behçet's syndrome, such therapy could have had severe adverse consequences if the correct diagnosis was MS. Early studies of TNF inhibition in MS revealed dramatic worsening of the disease both in terms of clinical symptoms and radiologic findings shortly after the initiation of treatment (26). Thus, despite the substantial rationale for the use of TNF inhibition in MS that appeared to exist at one time, this treatment approach is now strongly contraindicated. At this point, the patients' clinicians found themselves at a diagnostic and therapeutic impasse.
During this period of deliberation related to the choice of treatment, the patient was admitted on 2 other occasions for apparent worsening of her neurologic disease. The first readmission was prompted by the development of right face allodynia and decreased temperature sensation in the right arm. At that time, repeat MRI showed findings suggestive of tumefactive MS, a deeply troubling finding. Numerous enhancing hyperintensities existed throughout the white matter with a prominent tumefactive lesion in the left periventricular white matter (Figure 3). This study highlighted the progression of the patient's disease despite high doses of glucocorticoids. The patient's progression while receiving therapy over a period of weeks essentially excluded a monophasic, self-limited disorder such as ADEM. The patient's second readmission was precipitated by the return of numbness in the pelvic area and right leg. During both hospital admissions, the patient was treated with glucocorticoid pulses, to the effect that over a 6-week period she received 15,000 mg of methylprednisolone in the form of pulse doses. After her third hospitalization, the patient was discharged on prednisone 60 mg daily.
Diagnosis, treatment, and subsequent course
Approximately 6 weeks after stopping her MTX, the patient presented with an oral ulcer (Figure 4), thereby removing the major argument against Behçet's syndrome. Two months after her initial hospitalization, the patient received her first dose of infliximab (5 mg/kg). She tolerated this medication well. MTX (25 mg/week) was resumed because it was now thought that her previous ulcerations had been attributable to Behçet's syndrome rather than MTX toxicity. In addition, concomitant MTX appears to play an important role in minimizing the human antichimeric antibody response in patients treated with infliximab (27, 28). She was also treated with folic acid (1 mg/day).
The patient responded dramatically to the addition of infliximab to her treatment regimen. By the time of her third intravenous infusion 6 weeks after the initiation of treatment, the patient had been able to taper her daily prednisone dose to 10 mg. Her ocular and neurologic symptoms improved quickly, and serial MRI studies showed resolution of her brain and spinal cord lesions (Figure 5).
Our case is a classic illustration of the ancient Buddhist allegory of the blind men touching the elephant. In that tale, a group of blind men palpated different parts of the same elephant and developed belligerently different opinions about the nature of the animal they had examined. In many respects, because none of the principal diagnoses under consideration in this case have pathognomic features or incontrovertible diagnostic criteria, the rheumatologist, neurologist, and ophthalmologist were rather like the group of blind men in the tale, each favoring a condition that fell within the purview of his respective specialty, e.g., Behçet's syndrome, a demyelinating disorder, or VKH syndrome. Differentiating among these conditions is important because their treatments differ dramatically and the failure to institute effective therapy in a timely manner can lead to poor outcomes.
This case underscores a number of important points that are useful in distinguishing between Behçet's syndrome and demyelinating disorders. First, Behçet's syndrome can occur with few or even no oral ulcers. The absence of oral ulcers constituted strong grounds for reconsidering the diagnosis, but the eventual emergence of this disease complication clinched the diagnosis. Our patient's use of MTX, also a cause of oral ulcers, was the type of “red herring” that is common to many complex, multiorgan system diseases that require immunosuppression.
Second, our patient's degree of uveitis was too severe for MS. MS can be associated with inflammation of the pars plana, also called intermediate uveitis, but panuveitis should direct diagnostic considerations elsewhere. Our patient's CSF pleocytosis was also highly uncharacteristic of MS.
Finally, the availability of TNF inhibitors has dramatically altered the approach to treating severe cases of Behçet's syndrome with CNS disease or inflammatory eye disease of the posterior segment. Many authorities on Behçet's syndrome now regard TNF inhibition combined with glucocorticoids as the first-line approach to treatment in these scenarios (23, 24). Although long-term treatment outcome studies are required, it is possible that this approach will control the inflammatory process more effectively than conventional treatment regimens, with fewer adverse effects.
FOLLOWUP ON THE PATIENT
Eighteen months after initiating infliximab, the patient has maintained a stable disease course without recurrence of either ocular or CNS inflammation. Recent imaging of her brain and cervical spinal cord shows no acute lesions. She has tapered her prednisone to 6 mg/day.
Behçet's syndrome with panuveitis and parenchymal brain disease.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Stone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Stone, Papaliodis, Costello.
Acquisition of data. Stone, Papaliodis, Costello.
Analysis and interpretation of data. Stone, Papaliodis, Costello.