Elsberg syndrome

DISCUSSION

ES is poorly defined and rarely reported, but it is probably frequently unrecognized. Based on the historical literature and our clinical experience, we formulated objective criteria for ES with 4 different levels of certainty (table 1). Radiculitis, manifest either clinically (table 1, A1), radiologically or electrophysiologically (table 1, A2) is required. A secure diagnosis is possible when evidence for infection by a causative virus is demonstrated and alternative causes excluded, but given the sensitivity of the serologic and virologic studies⁹ and frequent delay in obtaining appropriate samples, clinical and radiologic evidence may suggest ES regardless of the microbiologic information. For this reason, we established criteria for clinically definite, probable, and possible ES (see supportive feature in table 1, B1–B5). In addition, we identified red flags that are cautionary but not exclusionary as well as exclusionary criteria (table 1, C and D).

The onset of ES was consistently acute in our cohort; insidious onset and evolution suggest alternative explanations such as sarcoidosis or neoplasm. Suspected cauda equina involvement, which leads to urinary retention, is confirmed with MRI and/or EMG. Concomitant myelitis detected radiologically or clinically further supports the diagnosis. Myelitis, associated with many inflammatory CNS conditions such as MS, NMO, anti-MOG antibody myelitis, sarcoidosis, and others, is not usually associated with radiculitis, whereas radiculitis is a required feature for the diagnosis of ES.

We did not identify pathognomonic or specific neuroradiologic findings. Nevertheless, some features were typical and could help distinguish ES from other disorders. Spinal cord lesions were commonly multiple and discontinuous, usually not expansile, and centrally or ventrally positioned in the cord. Unlike the imaging usual pattern of dural arteriovenous fistula, which can also cause both upper and lower motor neuron problems, the cord lesions in ES are not consistently located in the most caudal portion of the conus. Dural arteriovenous fistula lesions, in contradistinction to ES, are usually continuous, extending rostral from the lowermost portion of the conus, involve the most of the thickness of the cord, and are commonly associated with swelling. Nerve root enhancement was sometimes diffuse and sometimes limited to ventral or dorsal roots. It was always smooth and continuous and never nodular or plaque like as can be seen with neoplastic nerve root lesions.¹⁰ Nerve root enhancement often occurred contemporaneously with spinal cord involvement, although either nerve root enhancement or spinal cord parenchymal signal abnormality could predominate; in some cases, root enhancement occurred at a later point of the illness as cord lesions were resolving. Finally, plaque or subpial cord enhancement, typical of granulomatous conditions,¹¹ did not occur in patients with ES.

CSF examination demonstrated lymphocytic pleocytosis in 15 patients (50%), and in 3 of those (20%), neutrophils exceeded 5%.

Although HSV infection is widely believed to be responsible for a majority of cases, almost half of the cases (13/30) were never investigated for the presence of a viral infection even though lumbar puncture was performed, indicative of the low level of diagnostic suspicion for an infectious etiology for this condition. Furthermore, when PCR was performed, only 2 of the 30 (7%) were positive in the CSF and 1 from a genital swab. Despite CSF viral detection being considered the diagnostic gold standard, its diagnostic accuracy is imperfect in real-life settings,^9,12 with a negative predictive value of 82% and a positive predictive value of 54% in one study.⁹ Therefore, a negative result cannot absolutely exclude the presence of infection. Furthermore, rapid viral clearance from the CSF has been shown for HSV and VZV infections.¹³ The highest yield of viral detection by PCR occurred in samples obtained 3–14 days after symptom onset.⁹ In our cohort, samples were acquired outside this interval in 14 of the 18 cases (78%); the only 2 positive CSF PCR samples were obtained at days 11 and 37. Of the 3 patients who experienced an HSV infection immediately preceding ES, only 1 (33%) was tested within 14 days and 1 at day 15; none were positive for HSV infection in the CSF and 1 tested positive only from a genital swab.

Reported experience with CSF PCR in patients with ES is mostly limited to case reports and sometimes other viral detection methods, such as serology or culture, have been used.⁵ Antibody studies may be particularly useful when CSF is obtained late (e.g., >14 days) in the course of the disease. Demonstration of intrathecal production of HSV- or VZV-specific immunoglobulin G (IgG) antibodies can be diagnostic.^14,15 Reliance on an antibody index comparing virus-specific IgG levels in CSF and serum with correction for blood-brain barrier leak using either the CSF/serum albumin ratio or the ratio of CSF/serum antibody titers of a nonpathogenic virus ensures that serum HSV or VZV antibodies have not reached the CSF by means of a sink mechanism. Although rarely demonstrated, the presence of virus-specific immunoglobulin M (IgM) in the CSF is strongly indicative of acute or active chronic CNS infection as these antibodies do not tend to cross the blood-brain barrier.

The 2 patients with a positive CSF PCR were positive for VZV. VZV may be considered an etiologic agent of ES,¹ but is also recognized to be a cause of myelitis and/or myeloradiculitis occurring elsewhere in the spinal cord. The 2 patients with herpes zoster detection experienced more widespread involvement of the spinal cord than did other Elsberg cases. The first patient, who was immunocompetent, had a few discrete lesions higher in the cord and also had encephalitic manifestations; the second patient, who was HIV positive and immunocompromised, had a longitudinally extensive lesion spanning up to 9 vertebral segments of the thoracic spine and had evidence of meningeal irritation and necrotic cord damage. Ascending necrotic myelitis has been described in the setting of HSV2.¹⁶ Although the patients with VZV meet the criteria for ES, encephalitic symptoms as well as long thoracic and cervical cord MRI lesions and meningeal irritation may be considered red flags, and caution in the diagnostic process should be maintained before providing a final diagnosis.

HSV and VZV are treatable when acyclovir is initiated early, but the potential benefits of treatments with antiviral drugs have not been documented. In our cohort, none of the 5 patients with follow-up who received acyclovir experienced a fatal outcome. Yet, one patient treated with both acyclovir and corticosteroids had no clinical recovery as did one patient who received corticosteroid treatment alone and another who received neither (table 4). Therefore, superiority of acyclovir treatment cannot be proven. Nonetheless, acyclovir treatment was started only in 6 patients, whereas high-dose corticosteroids were administered as primary treatment in 15 patients, illustrating the low index of suspicion for this condition and the tendency to treat as an idiopathic inflammatory condition.

The study is limited by its retrospective nature. Because of the referral pattern of patients to our institution, patients were evaluated initially at outside institutions and as this study was retrospective, investigations were not standardized. Potentially, we did not capture all cases by our electronic search strategy. The proportion of laboratory-supported definite cases and of patients with proven HSV infection was low. This might reflect low rates of awareness of this syndrome and consequent low proportion of cases with acute and convalescent serology results. Limitations of sensitivity of viral isolation methods particularly when samples are obtained late in the course may be an additional contributor. Perhaps, next-generation sequencing may enhance diagnostic sensitivity as already shown with other infections.¹⁷

We recognize that the scientific literature is moving away from eponymous definitions. Our intent was not to entrench an eponymous definition, but to formalize diagnostic criteria that are flexible to aid in the identification of patients with combinations of radiculitis and caudal myelitis who have potentially treatable viral infections after considering clinical and radiologic clues that identify other potential etiologies for this syndrome. Improved testing and virus identification methodologies may establish the role of antiviral treatment.

ES is a definable condition that may be responsible for approximately 5%–15% of patients with CES and myelitis based on our review of cases seen at the Mayo Clinic. It is usually self-limited but commonly leaves some degree of permanent neurologic deficit and in one instance led to a fatal outcome. Although radiologic findings are not specific, they can help to rule out competing diagnoses, such as dural arteriovenous fistula, sarcoidosis, and other conditions. When both enhancement of cauda equina and signal abnormality of the distal spinal cord occur acutely, Elsberg may be a common cause of the syndrome. The diagnostic criteria that we formulated may bring attention to this condition and permit a more precise diagnosis when integrated with tests to exclude other mimics. Detection of viral infection is useful, but sensitivity appears to be low. Treatment with acyclovir is appropriate even in the absence of demonstration of viral infection given the favorable risk-benefit profile of this drug.