Didier Cros, M.D., R. Gilberto Gonzalez, M.D., Ph.D., and Eugene J. Mark, M.D.
Presentation of Case
Dr. Sang-Woo (Steve) Han (Neurology): A 37-year-old woman was seen in the emergency department of this hospital because of a seizure. Four months earlier, episodes of vertigo began to occur several times a week that lasted up to several hours and were associated with nausea and vomiting. She was evaluated in the emergency department of another hospital; meclizine was prescribed, and she was instructed to follow up with her primary care physician. During the next 3 months, she had episodes of vertigo several times per week that were associated with tinnitus, diminished hearing, a sense of fullness in her right ear, and difficulty walking.
The results of otoscopic and audiographic examinations by an otolaryngologist were normal, with no cranial-nerve deficits; a diagnosis of endolymphatic hydrops was made, and a low-salt diet was recommended. Five weeks before admission, computed tomographic (CT) scanning of the sinuses revealed mild mucosal thickening of the maxillary sinuses with mild inflammatory changes in the ethmoid sinus. Triamterene and hydrochlorothiazide were begun and meclizine was continued, with partial relief of symptoms. One month before admission, magnetic resonance imaging (MRI) of the brain showed a focus of enhancement, 2 mm in diameter, in the deep right internal auditory canal, a finding consistent with an intracanalicular schwannoma, and several foci of hyperintensity on T2-weighted images in the frontal white matter and subinsular cortex bilaterally, findings consistent with nonspecific gliosis. Formal vestibular testing with electrocochleography and otolaryngology follow-up were scheduled.
Approximately 2 weeks later (2 weeks before admission), the patient awoke one morning with right-sided facial weakness. Three days before admission, another episode of dizziness occurred. On the morning of admission, the patient's daughter found her on a couch, unresponsive, with shaking extremities and drooling. The movements lasted approximately 5 minutes. Emergency medical services were called, and the patient was taken to the emergency department of another hospital. On arrival, the patient had regained consciousness; she recalled fatigue and a disturbance in balance immediately before the seizure but no headache.
On examination, the patient was agitated, confused, and fearful. The temperature was 37.1°C, the blood pressure 114/78 mm Hg, the pulse 122 beats per minute, the respiratory rate 22 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. The height was 157.5 cm, and the weight 44.5 kg. She was able to follow simple commands; her speech was garbled. There was a right facial droop; the deep-tendon reflexes were 3+ throughout, and spasticity and clonus were evident in the right leg. A complete blood count; levels of serum glucose, electrolytes, calcium, potassium, and magnesium; and liver- and renal-function tests were normal. An electrocardiogram showed sinus tachycardia. Lorazepam and phenytoin were administered intravenously. CT of the head, without the administration of contrast material, showed no intracerebral hemorrhage. After the CT scan, the patient had severe pain in the left hip, and morphine sulfate and additional lorazepam were given. She was transferred to this hospital by ambulance approximately 7 hours after her arrival at the other hospital.
The patient's mother reported that the patient had recently had a headache, ear pain, and left hip pain and that her appetite had been poor. There was a history of a febrile seizure in childhood. Six years earlier, she had had a traumatic fracture of the left hip; 3 years after that, a total hip replacement was performed because of osteonecrosis. She had had a tonsillectomy, a cone biopsy of the cervix, and cesarean sections. Amenorrhea had developed 18 months earlier. A test for human immunodeficiency virus (HIV) had been negative. She was of native Alaskan heritage and had been adopted as an infant. Her children were healthy; there was no information about her other biologic relatives. She was single, lived with her three children, and worked in sales. She drank alcohol daily, smoked cigarettes, and did not use illicit drugs. She had possible allergies to codeine and penicillin. Medications included meclizine, triamterene, and hydrochlorothiazide.
On examination, the patient was initially somnolent but arousable; she later became agitated, belligerent, and uncooperative. The temperature was 36.6°C, the blood pressure 95/64 mm Hg, the pulse 100 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. Her affect ranged from angry to tearful. She was oriented to self but not to place or time. Dentition was poor; the abdomen was soft with diffuse mild tenderness, and the remainder of the general physical examination was normal. Her speech was fluent. There was asymmetry in the facial muscles, with right-sided weakness. The pupils were reactive; the extraocular movements were intact, with horizontal nystagmus and saccadic breakdown of pursuit, without ptosis. Hearing was intact; the tongue protruded in the midline, and there was mild dysarthria. Other cranial-nerve functions and attention, memory, and ability to make calculations could not be assessed. There was limitation of movement in the left leg because of hip pain; motor strength was otherwise normal. The arms and legs were hyperreflexic; plantar reflexes were extensor. Posture, stance, stride, and arm swing were markedly impaired. She walked with her feet inverted and on her toes, with small steps.
The complete blood count; levels of serum electrolytes, glucose, bilirubin, and protein; and liver- and renal-function tests were normal. Serum and urine pregnancy testing was negative. Analysis of the urine was normal except for a toxicology screening, which was positive for opiates. Radiographs of the chest, hip, pelvis, and foot were normal. MRI of the brain, performed after the administration of lorazepam, was limited by motion-related artifacts but revealed hyperintensities of the medial temporal lobes on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images bilaterally and in the posterior gyri recti, more prominently on the left side than on the right. There was nearly complete opacification of the right maxillary sinus. She was admitted to the Neurology Service.
During the first 3 days, the patient remained agitated, belligerent, and confused, requiring the use of leather physical restraints. Phenytoin, magnesium, acyclovir, folate, thiamine, a transdermal nicotine patch, and dalteparin were administered. Lorazepam and olanzapine were given for agitation, and hydromorphone and morphine sulfate as needed for pain. On the third hospital day, the patient was evaluated by a psychiatrist. She was somnolent and confused and not oriented to place or time, with poor memory. She was easily distracted, with slurred and slowed speech and tangential thought. The C-reactive protein level was 23.2 mg per liter (normal range, <8.0);> rate, electrolyte levels, and electroencephalography were normal. Olanzapine was discontinued and haloperidol administered.
On the fourth hospital day, her mental status improved and the restraints were removed; she was pleasant and engaged, with linear thought, recall of three of three objects at 5 minutes, and knowledge of past presidents. Extraocular movements were intact, and there was no nystagmus. There was weakness of the right lower facial muscles and increased extensor tone in both legs, the ankles were plantar flexed, and the feet were inverted. Motor strength was normal, although it was difficult to fully assess in the left leg because of hip pain. The sensory examination was normal. There was hyperreflexia in the arms and legs and sustained clonus in the left ankle, and the plantar reflexes were extensor. The gait was abnormal because of hypertonia, with circumduction of the left leg to avoid dragging the foot.
A lumbar puncture was performed (Table 1). Cytologic examination of the fluid revealed increased lymphocytes, which were predominantly mature-appearing. A tuberculin skin test was negative. Flow cytometry showed T cells with a CD4:CD8 ratio of 3:4. Repeated MRI revealed extensive, multifocal regions of nodular enhancement involving the leptomeninges and ependyma, along the lenticulostriate vessels, hippocampi, and optic nerves bilaterally, within the left rectus gyrus, along the optic chiasm and pituitary stalk, and within the right internal auditory canal. Hyperintensities of the mesial temporal lobes and left rectus gyrus were again noted on T2-weighted and FLAIR images. Magnetic resonance angiography of the head and neck were normal.
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On the seventh hospital day, MRI of the spine revealed enhancing leptomeningeal nodules involving the cervical spinal cord and conus medullaris, as well as parenchymal involvement in the cervical spinal cord. CT scanning of the chest, abdomen, and pelvis showed bilateral hilar and mediastinal lymphadenopathy, slight thickening of the bronchial walls, and small retroperitoneal and mesenteric lymph nodes. The antinuclear-antibody (ANA) test was positive at 1:320 in a speckled pattern. Serum levels of thyrotropin, prolactin, and follicle-stimulating hormone were normal, and a rapid plasma reagin test was negative. Acyclovir and dalteparin were stopped.
A transbronchial biopsy of the lung on the 12th day revealed mild nonspecific interstitial fibrosis without evidence of granulomas or cancer. The patient was discharged later that day at her request, pending the results, and was readmitted 3 days later. Biopsies of the dura and brain were performed the next day; pathological examination of the biopsy specimens revealed normal cortex and meninges. The serum level of angiotensin-converting enzyme (ACE) was 36 U per liter (normal range, 7 to 46).
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Didier Cros: This previously healthy 37-year-old woman had a 4-month history of neurologic manifestations, including vertigo, nausea, facial weakness, bilateral pyramidal syndrome, and a seizure, which were suggestive of multifocal pathology in the nervous system, and long-standing amenorrhea that may indicate endocrine dysfunction. She was afebrile and HIV-negative. May we review the radiologic studies?
Dr. R. Gilberto Gonzalez: Attempts at MRI of the brain on admission were marred by motion artifact, despite sedation. Repeated MRI on hospital day 4 (Figure 1A and 1B) showed extensive signal abnormalities and abnormal enhancement involving the leptomeninges, the ependyma, and the parenchyma in both a linear and nodular pattern. There was thickening and diffuse linear and nodular enhancement of the pituitary stalk. MRI of the spine on day 7 (Figure 1C) revealed involvement of the entire spine by the enhancing abnormality, with both leptomeningeal enhancement and linear and nodular enhancement of the spinal cord parenchyma; most prominent in the upper cervical area was the nodular enhancement of the cervical spinal cord. Chest CT performed the same day revealed pretracheal and bilateral hilar lymphadenopathy (Figure 1D).
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Dr. Cros: A large number of disorders may affect the leptomeninges and the brain and spinal cord parenchyma and may ensheath the cranial nerves and spinal roots. The documentation of mediastinal and hilar lymphadenopathy in this patient helps to focus the differential diagnosis. I participated in the care of this patient, and our considerations included neoplastic, infectious, and inflammatory and granulomatous disorders.
Neoplastic Disorders
Metastases of systemic cancer were a concern at the time of presentation, even though there was no known malignant condition in this patient. Breast, lung, and gastrointestinal cancers, melanoma, and lymphomas account for the majority of primary tumors that metastasize to the meninges. In the absence of known cancer, and with the normal results of the clinical examination of skin and breasts and of the chest, abdominal, and pelvic CT scans, the suspicion of a systemic lymphoma affecting the intrathoracic lymph nodes was heightened. Primary central nervous system (CNS) lymphoma was also considered, since leptomeningeal involvement occurs in 40% of patients with primary CNS lymphoma and is the initial presentation in about 8% of patients.1,2
Examination of the cerebrospinal fluid is central to the diagnosis of meningeal carcinomatosis. The spinal fluid was obtained by lumbar puncture, which is optimal for the assessment of possible malignant infiltration, since the cauda equina is often affected by the pathologic process. False negative results may occur if cerebrospinal fluid is obtained from an unaffected compartment of the subarachnoid space. Cytologic examination in this case revealed no malignant cells, and flow cytometry showed no evidence of lymphoma.
Infectious Disorders
A number of infectious diseases may affect the leptomeninges. Tuberculosis has a predilection for the leptomeninges of the base of the brain and frequently affects the cranial nerves, causing a vasculitis of the penetrating arteries that may result in strokes and also causing obstruction to the flow of cerebrospinal fluid that results in hydrocephalus. Although rare (fewer than 200 cases per year in the United States), tuberculosis of the CNS should be diagnosed promptly, since the prognosis remains poor despite efficacious medications. Examination of the cerebrospinal fluid revealed no acid-fast bacilli, but this examination should be repeated if clinical suspicion is high. In this patient, the diagnostic suspicion was lessened by the chronicity, absence of fever, normal sedimentation rate, absence of cavitary lesions in the lungs, and negative purified-protein-derivative tuberculin test.
Syphilis was also considered, since early neurosyphilis may result in a pathologic pattern similar to that documented by the results of imaging and cerebrospinal fluid examination in this patient. Florid leptomeningeal inflammation causes multiple cranial neuropathies, infectious vasculitis with possible stroke, and hydrocephalus. Parenchymal involvement in the brain and spinal cord may result from the development of syphilitic gumma. This diagnosis was ruled out by the nonreactive serum rapid plasma reagin test and by a Venereal Disease Research Laboratory test of cerebrospinal fluid.
Neuroborreliosis may cause clinical patterns similar to those of syphilis, including meningitis and encephalomyelitis, which may be more common with the strains of borrelia in Europe than with those in North America.3 In fact, the pathological resemblance of meningovascular syphilis and neuroborreliosis has been documented.4 Primary infection with borrelia is much more common than syphilis, particularly in New England. Neurologic manifestations develop in 15% of patients with Lyme disease and include cranial neuropathies, painful radiculopathies, and lymphocytic meningitis. Generalized neuropathy indistinguishable from the Guillain–Barré syndrome may be seen. In this patient, testing for antibodies and for borrelia DNA by polymerase chain reaction was negative, ruling out Lyme disease.
Inflammatory and Granulomatous Disorders
In Wegener's granulomatosis, meningitis may occasionally be the initial clinical presentation,5 although peripheral and cranial neuropathies are the most common neurologic manifestations. Wegener's granulomatosis generally affects the upper and lower airways and the kidneys. The normal sedimentation rate and the absence of lung lesions in this patient argued against this diagnosis, as did a sensitive and specific test for antineutrophil cytoplasmic antibodies, which was negative.
The possibility of systemic lupus erythematosus (SLE) was discussed, since the ANA test was positive at 1:320. Leptomeningeal involvement and myelopathy can be seen in patients with lupus, albeit rarely.6 Other neuropsychiatric manifestations in SLE include stroke, transient ischemic attacks, seizures, psychosis, cognitive disorders and dementia, and delirium7; this patient had many of these manifestations at the time of her admission. Primary neurologic presentations of SLE occur in 24% of cases,6 usually in patients with a positive ANA test and anti–double-stranded DNA antibody.
Other inflammatory disorders were also considered. Rheumatoid arthritis can cause CNS disease, but this usually occurs in patients with severe rheumatoid arthritis with a positive rheumatoid factor.8 Sjögren's syndrome on rare occasions causes meningoencephalitis, but the autoantibodies correlating with Sjögren's syndrome were absent.
Neurosarcoidosis
A diagnosis of neurosarcoidosis was considered most likely, in view of both the pattern of CNS involvement documented by MRI and the mediastinal and hilar lymphadenopathy. Neurosarcoidosis is a chronic granulomatous disease that varies in incidence around the world and among racial and ethnic groups — in the United States, the adjusted annual incidence among blacks is about three times as high as that among whites.9 I am not aware of reports of the incidence in Inuits. The disease involves patients of all ages but most commonly is seen in young adults, such as this patient. Sarcoidosis most commonly affects the lungs, eyes, and skin. According to autopsy studies, the nervous system is affected in up to 25% of patients,10 but only about half these patients have clinical neurologic manifestations.2 About 40% of patients with neurosarcoidosis have previously diagnosed sarcoidosis in another organ, most commonly the chest or anterior uvea, unlike our patient.11,12 Cranial neuropathies, particularly optic and facial neuropathies, are the most common manifestation of neurosarcoidosis and are seen in 30 to 40% of patients with neurosarcoidosis. Spinal cord and meningeal involvement, seen in this patient, are also common.12 Rarely, psychosis may occur, as seen in this patient.
Findings on brain MRI typically include multiple white-matter lesions, with or without meningeal enhancement, but a single parenchymal lesion, an optic-nerve lesion, or spinal cord lesions may be seen or the findings may be normal.11 Involvement of the hypothalamus, pituitary, or both occasionally occurs in patients with neurosarcoidosis, as it did in this patient, and may have been responsible for the amenorrhea noted in this patient.1,12 ACE is produced by sarcoid granulomas, and the serum level is elevated in 60% of patients with sarcoidosis. A normal serum ACE level, as seen in this patient, does not eliminate this possibility of sarcoidosis. The sensitivity and specificity of ACE levels in the cerebrospinal fluid are unknown.
The diagnosis of neurosarcoidosis should be confirmed by microscopical examination of a biopsy specimen. Since noncaseating granulomas are not pathognomonic of sarcoidosis, the pattern of neurologic and organ involvement should be consistent with sarcoidosis, and alternative diagnoses should be ruled out. The diagnosis of neurosarcoidosis is considered definite if granulomas are seen on biopsy specimens of the brain or meninges, and probable if the pathological evidence is obtained on non-CNS tissue such as the lung or lymph nodes. In this patient, after the lung biopsy showed no evidence of granulomas or cancer, we elected to perform a biopsy of the brain and meninges, since in a patient with this constellation of clinical findings, detection of a noncaseating granuloma in the brain would have secured a diagnosis of sarcoidosis and ruled out other diagnoses. The results of examination of the biopsy specimens of the brain and meninges were normal; therefore, the natural target of our examination became the mediastinal nodes.
Dr. Didier Cros's Diagnosis
Neurosarcoidosis.
Pathological Discussion
Dr. Eugene J. Mark: Mediastinoscopy with biopsies of several enlarged lymph nodes was performed. On histopathological examination, compact, non-necrotizing granulomas occupied approximately 80% of the lymph-node tissue (Figure 2A). The lymph node had areas of sclerosis (Figure 2B), and the hyaline collagen was wrapped around individual granulomas. All the granulomas were histologically similar, which has been described as a feature of the granulomas in sarcoidosis, as distinct from granulomas due to mycobacterial or fungal infection.13,14 Special staining and cultures of the biopsy specimens of the lymph nodes were negative for microorganisms. The combination of the histopathological, clinical, and radiographic findings indicates a diagnosis of sarcoidosis.13,14
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The distribution of granulomas in sarcoidosis differs somewhat in various organ systems. In the lung, the granulomas are preferentially distributed along lymphatic pathways.15,16,17 In the CNS, the granulomas of sarcoidosis preferentially involve the meninges, as was the case with this patient. They can also involve the ependyma with extension into the choroid plexus and form nodules and tumorous masses that may extend into the underlying parenchyma.18,19
Dr. Nancy Lee Harris (Pathology): Dr. Sheth, will you tell us about your care and follow-up of this patient?
Dr. Kevin N. Sheth (Neurology): When the patient first arrived, she was floridly psychotic, and it took several days for us to obtain a thorough history and physical examination. It was not clear whether her altered mental state was due to neurosarcoidosis, a postictal phenomenon, or a reaction to lorazepam. After the diagnosis of sarcoidosis was established, we began treatment with high-dose prednisone. She had a dramatic response, with resolution of her vertigo and gradual resolution of her neurologic symptoms; phenytoin was discontinued. Several months after beginning treatment with prednisone, her menstrual periods resumed. Eight months after she was discharged from the hospital, she had residual hyperreflexia, but her strength and gait were normal; prednisone was discontinued.
Anatomical Diagnosis
Neurosarcoidosis.
Dr. Gonzalez reports receiving lecture fees from Bayer and General Electric. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Neurology (D.C.); the Division of Neuroradiology, Department of Radiology (R.G.G.); and the Department of Pathology (E.J.M.), Massachusetts General Hospital; and the Departments of Neurology (D.C.), Radiology (R.G.G.), and Pathology (E.J.M.), Harvard Medical School.
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