- Email: [email protected]
Osmotic demyelination syndromes: Central and extrapontine myelinolysis
684
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
Osmotic demyelination syndromes: Central and extrapontine myelinolysis S. Huq a
a,b,*
, M. Wong
c,d
, H. Chan
c,d
, D. Crimmins
c,d
Department of Neurology, Gosford District Hospital and Royal North Shore Hospitals, Pacific Highway, St Leonards, NSW 2065, Australia b Department of Medicine, University of Sydney, Camperdown, NSW, Australia c Department of Neurology, Gosford District Hospital, Gosford, NSW, Australia d Departments of Neurology and Medicine, University of Newcastle, Callaghan, NSW, Australia Received 16 December 2005; accepted 21 February 2006
Abstract Osmotic demyelination syndromes are often progressive disorders, with clinical features ranging from a mild tremor or dysarthria to a progressive quadraparesis. Although rapid correction of serum sodium is known to be a potent causative factor, additional pathogenic factors exist, which appear critical in predisposing pontine and extrapontine glia to osmotic stress. Interestingly, several cases of osmotic demyelination have emerged where serum sodium was found to be within normal limits and minimal or no correction of a hypo or hypernatraemic state was implemented. We describe two cases – one of extra pontine and another of central-pontine myelinolysis, both of which have occurred in the context of relatively normal serum sodium. The first case illustrates the association of extrapontine myelinolysis with the traditional risk factor of alcoholic cirrhosis and intravenous fluid resuscitation, while the second, more unusual case, describes a patient who developed central pontine myelinolysis possibly in association with alpha interferon therapy. 2006 Elsevier Ltd. All rights reserved. Keywords: Central Pontine Myelinolysis; Chronic Liver Disease; Hyponatraemia; Alpha Interferon
1. Introduction Osmotic demyelination syndromes, which consist of central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), are rapidly progressing, often fatal focal symmetric syndromes, with clinical features ranging from a mild tremor or dysarthria to a progressive quadraparesis and a locked-in syndrome. The aetiology of osmotic demyelination is not well understood. Although rapid correction of serum sodium in the context of chronic hyponatraemia has been implicated as a potent causative factor,1 it is clear now that additional pathogenic factors exist, which are critical in predisposing pontine and extrapontine glia to osmotic stress.2 Among these, the most prominent appear to be significant alcohol use and orthotopic liver transplantation.3,4 Interestingly, several cases of CPM and EPM have been described in the literature where serum sodium was found to be within normal limits.5 We describe two cases, one of extra pontine and another of central-pontine myelinolysis, both of which have occurred in the presence of chronic liver disease and normal serum sodium. The first case illustrates the association of extrapontine myelinolysis with the traditional risk factor of alcoholic cirrhosis and intravenous fluid resuscitation. The second, more unusual
*
Corresponding author. Tel.: +612 9926 8656; fax: +612 9439 8418. E-mail address: [email protected] (S. Huq).
case describes a patient with chronic liver disease secondary to viral hepatitis, who developed CPM with normal serum sodium levels, no correction of electrolyte status, and the possible additional risk factor of alpha interferon therapy. 1.1. Case 1 A 56-year-old man with known alcoholic liver disease was brought into the emergency department. He was unconscious on arrival and reported to have been drinking heavily. Vital signs were normal, and he was afebrile. On examination he was acutely delirious. Neurological examination revealed equal but sluggishly reactive pupils. He was hypertonic in both limbs, and his reflexes were brisk with bilaterally upgoing plantar responses. Power, coordination and sensation could not be formally assessed, but he was moving all limbs and withdrawing from pain. The remaining systemic examination was unremarkable. He was admitted to an intensive care unit (ICU) where high flow oxygen and intravenous fluids were administered. To investigate his poor level of consciousness, a urine drug screen and a septic work-up was performed, both of which were negative. His blood alcohol level was 2 mmol/L (0– 4.3 mmol/L). Blood glucose was measured at 5.1 mmol/L (3.5–8.0 mmol/L). A full blood count, electrolytes, urea and creatinine, calcium, magnesium and phosphate, thyroid function test and troponin were all within normal limits. Liver function tests were consistent with the history of
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
alcoholic cirrhosis, with an elevated bilirubin, alkaline phosphotase and gamma-glutamyl transferase. Serum sodium was 140 mmol/L (135–149 mmol/L) at presentation and remained within normal limits through the entire admission. Over the next 24 h, further management with intravenous thiamine and vitamin supplementation was implemented and his level of consciousness gradually improved. Ceftriaxone was started for possible sepsis, as well as intravenous phenytoin for seizure prophylaxis. Formal neurological testing subsequently revealed ataxia, dysdiadochokinesis, and poor coordination bilaterally. Given persisting signs, further investigations were performed to exclude a brainstem infarct, meningoencephalitis, subdural haematoma or hypoxic brain injury. Cranial CT scanning and a lumbar puncture were performed, both of which were normal. Finally, an MRI of the brain revealed multiple foci of hyper-intense long TR signals in the cerebral white matter, the corpus callosum and the cerebellar hemispheres bilaterally (Fig. 1a, b). However, there were no signal changes within the pons, and no loss of grey-white differentiation to suggest a hypoxic insult. These MRI findings were consistent with extra pontine myelinolysis. The patient had a fluctuating course of illness over the next 3 weeks and required high-level nursing care. By day 5 he was orientated to time and place, and speaking more fluently. His mental state gradually improved and he was finally discharged to a rehabilitation hospital on day 21 of admission. 1.2. Case 2 A 51-year-old man presented for assessment with a 4-week history of gradual onset of dysarthria, fine-move-
685
ment incoordination and unsteadiness of gait. These symptoms deteriorated during the day and improved after rest. His background history included hepatitis C infection (genotype 3a), acquired 15 years previously through intravenous drug use, and complicated by cirrhosis. His other medical history was significant for type 2 diabetes mellitus of 10 years duration, complicated by retinopathy and nephropathy. Two weeks prior to admission, he had just finished a 6-month course of alpha interferon treatment for the viral hepatitis. He reported being completely abstinent from alcohol for at least two years prior to commencement of this treatment. On examination, the patient was alert and orientated with normal vital signs. Neurological examination revealed normal tone but brisk reflexes, especially in the lower limbs. The power of the left leg was reduced to 4/5. Coordination was impaired on the left side with past pointing in the left hand and dysdiadochokinesis in the left leg. Sensory and cranial nerve examinations were unremarkable. He also had peripheral stigmata of chronic liver disease with ecchymoses, spider naevi, and tender hepato-splenomegaly. Given the above neurological findings, the diagnostic possibilities included a brainstem or cerebellar infarct or neoplasm, cerebellitis, multiple sclerosis or a late-onset hereditary ataxia. Laboratory tests showed a normal serum sodium level of 139 mmol/L (135–145 mmol/L). Serum sodium, which was checked quarterly while on alphainterferon therapy, had always been within normal limits prior to admission. Liver function tests revealed a transaminitis consistent with the history of chronic hepatitis. Alpha-foetal protein levels were normal. Neurological work-up including a lumbar puncture and cranial CT scan were normal. Magnetic resonance imaging demonstrated
Fig. 1. T2 axial (A) and FLAIR (B) MRI of cerebellum and brainstem (case 1). In the cerebellar hemispheres bilaterally, there are hyperintense long TR signal abnormalities (arrows) involving the white matter, fairly symmetrical and extending to the posterior margin of the middle cerebellar peduncles, particularly on the right side, consistent with extrapontine myelinolysis.
686
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
Fig. 2. T2 axial (A), and diffusion weighted (B) MRI of the cerebrum and pons (case 2). Symmetrically within the central pons there are hyperintense long TR signals sparing the periphery, without mass effect (arrows), consistent with central pontine myelinolysis.
hyperintense long TR signals within the central pons sparing the periphery (Fig. 2a, b). These MRI features were consistent with central pontine myelinolysis. No particular treatment apart from supportive measures was initiated. The patient was reviewed regularly on a clinical basis as an outpatient. He remains well at 1-month follow-up, although the majority of his neurological findings persist. 2. Discussion Advances in neuroimaging, especially MRI, have allowed earlier detection of the characteristic lesions of CPM and EPM. The prevalence of this condition, once thought to be rare, is highlighted by a number of large series, with one demonstrating an incidence of 3/1000 in an unselected urban hospital population group.6 Evidence from clinical and laboratory data implicate hyponatraemia as a potent risk factor predisposing to CPM,7–9 and rapid sodium replacement has been implicated as one of the principal pathogenic stimuli to glial damage.10 The precise mechanism by which cellular injury occurs in CPM/EPM is speculative and the prevailing hypothesis implicates reduced adaptive capacity of neuroglia to large shifts in serum osmolarity.11,12 Critical discrepancies to this hypothesis are that most patients receiving even rapid sodium correction do not develop CPM.2 Conversely, mildly hyponatraemic patients whose rate of replacement never exceeded 11 mmol/24 h can develop CPM.13,14 A background predisposition thus appears to be central to the development of this clearly heterogeneous condition. Two conditions appear to be particular risk factors for the development of CPM/EPM. These include chronic alcohol abuse and
orthotopic liver transplantation.3,4 The latter group is particularly predisposed to CPM by virtue of operative and post-operative fluid resuscitation, co-existent renal disease and electrolyte derangement, and the use of cyclosporin A.4 Pathologically, CPM/EPM has been characterised by dissolution of the myelin sheaths and sparing of nerve axons within the central aspect of the basis pontis or extrapontine regions. Surprisingly, given the extent of glial cell death, there is a conspicuous absence of scavenger cells or inflammatory response, leading to the suggestion that cell death is mediated largely by apoptosis.15 Glial cells, the vulnerable cells in CPM, play a critical role in regulating extracellular osmolality and electrolyte balance in support of the neurones they envelop. In the face of an osmotic challenge, neuroglia activate energy-dependant cell surface pumps (eg. Na-K ATPase) to rapidly counteract the electrolyte derangement.2 In patients with liver failure, it is postulated that glia may inherently lack a plentiful supply of glucose or glycogen, hence relatively minor osmotic derangements lead to rapid depletion of cellular energy supply and cell death.2 This certainly appears to be the case with the two cases we describe, where despite a relatively normal serum sodium, both patients developed extensive demyelination. The second case is particularly interesting in this respect, as the patient developed CPM in the outpatient setting, in the absence of fluid resuscitation and relatively normal serum sodium. An increasing number of risk factors are being recognised for the development of osmotic demyelination, including adrenal insufficiency, malnutrition, chronic renal failure and haemodialysis, sepsis, and malignancy.2 As such, with more than one predisposing factor, CPM may
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
indeed develop in the absence of serum sodium fluctations. Case 2 clearly demonstrates this, where the patient had both liver disease and diabetic nephropathy. Furthermore, he underwent treatment with alpha-interferon. Alphainterferon has been associated with a number of adverse neuropsychiatric effects, including paraesthesia,16 seizure activity,16 depression, neuralgic amyotrophy and polyradiculopathy,17 and severe neuropathy.18 Given the above, we hypothesise that this patient may well have developed CPM as a result of a combination of events, where chronic liver disease and renal insufficiency acted as predisposing factors and the addition of a biological modulator lead to glial injury. To our knowledge, the association of interferon treatment with osmotic demyelinating syndromes has not been previously described. It is interesting to note that the patient developed CPM several months after commencement of interferon therapy. With the extensive use of alpha-interferon, adverse effects are increasingly being recognised as early-onset (within 3 months of therapy) such as depression and influenza-like symptoms, and lateonset (after 3 months), such as anterior ischaemic optic neuropathy and myasthenia gravis and sarcoidosis.19 Indeed, Finsterer et al.20 reported a case of multifocal leukoencephalopathy and sensory-motor polyneuropathy 16 years after the commencement of alpha-interferon therapy. We hypothesise that CPM might be a late-onset adverse event of alpha-interferon therapy, hence the development of symptoms several months after initiation of therapy. Prognostically, the osmotic demyelinating syndromes are highly heterogenous with complete recovery and reversal of MRI findings reported in some cases to progression and death in others. No specific treatment has been shown to convincingly halt the progress or reverse CPM/EPM. Although isolated case reports suggest that steroids21 or thyrotropin releasing hormone22 may be helpful, no randomised trials exist. A number of guidelines outlining the appropriate rate of sodium replacement in a hyponatraemic patient have been published;23,24 however, there is a distinct paucity of recommendations relating to the management of individuals with normal serum sodium at presentation. To date, prevention of osmotic demyelination remains the mainstay of treatment. The predominant view (arising largely from case studies)25 is that in individuals with one or more risk factors (severe systemic illness, alcoholism, liver transplantation, or malnutrition) should undergo frequent neurological assessment coupled with appropriate imaging (MRI vs. CT) to make the diagnosis. CPM/EPM needs to be particularly considered in individuals who fail to recover as expected after severe illness or in patients manifesting new ‘‘psychiatric symptoms’’ after severe illness.25 It is recommended that high-risk individuals, once identified, should receive prompt treatment with nutritional supplements, with exacerbating factors such as drugs and salt-losing nephropathies corrected.2 Finally, a multi-disciplinary neuro-rehabilitation program combined with symptomatic
687
treatment of any movement disorders (which sometimes accompany EPM) should be implemented to promote a complete functional recovery.
References 1. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. Arch Neurol Psychiatry 1959;81:154–72. 2. Ashrafian H, Davey P. A review of the causes of central pontine myelinosis: yet another apoptotic illness? Eur J Neurol 2001;8: 103–9. 3. Singh N, Yu VL, Gayowski T. Central nervous system lesions in adult liver transplant recipients: clinical review with implications for management. Medicine (Baltimore) 1994;73:110–8. 4. Yu J, Zheng SS, Liang TB, et al. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004;10:2540–3. 5. Mast H, Gordon PH, Mohr JP, et al. Central pontine myelinolysis: clinical syndrome with normal serum sodium. Eur J Med Res 1995;1: 168–70. 6. Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain 1979;102:361–85. 7. Victor M, Laureno R. Neurologic complications of alcohol abuse: epidemiologic aspects. Adv Neurol 1978;19:603–17. 8. Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988;34:351–60. 9. Verbalis JG, Martinez AJ. Neurological and neuropathological sequelae of correction of chronic hyponatremia. Kidney Int 1991;39: 1274–82. 10. Kleinschmidt-DeMasters BK, Norenberg MD. Neuropathologic observations in electrolyte-induced myelinolysis in the rat. J Neuropathol Exp Neurol 1982;41:67–80. 11. Sterns RH, Thomas DJ, Herndon RM. Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int 1989;35:69–75. 12. Verbalis JG, Gullans SR. Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. Brain Res 1993;606:19–27. 13. Riggs JE, Schochet Jr SS. Osmotic stress, osmotic myelinolysis, and oligodendrocyte topography. Arch Pathol Lab Med 1989;113: 1386–8. 14. Sterns RH, Baer J, Ebersol S, et al. Organic osmolytes in acute hyponatremia. Am J Physiol 1993;264:F833–6. 15. Newell KL, Kleinschmidt-DeMasters BK. Central pontine myelinolysis at autopsy; a twelve year retrospective analysis. J Neurol Sci 1996;142:134–9. 16. Smedley H, Katrak M, Sikora K, et al. Neurological effects of recombinant human interferon. Br Med J (Clin Res Ed) 1983;286: 262–4. 17. Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA 1984;252:938–41. 18. Bernsen PL, Wong-Chung RE, Janssen JT. Neuralgic amyotrophy and polyradiculopathy during interferon therapy. Lancet 1985;1 (8419):50. 19. Kreutzer K, Bonnekoh B, Franke I, et al. [Sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy: severe side effects of adjuvant interferon-alpha-therapy in malignant melanoma?]. J Dtsch Dermatol Ges 2004;2:689–94. 20. Finsterer J, Sommer O, Stiskal M. Multifocal leukoencephalopathy and polyneuropathy after 18 years on interferon alpha. Leuk Lymphoma 2005;46:277–80. 21. Nishino K, Yasuda T, Kowada M. [A case of central pontine myelinolysis with neurological recovery after administration of gluco corticoid]. No To Shinkei 1991;43:483–8.
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22. Wakui H, Nishimura S, Watahiki Y, et al. Dramatic recovery from neurological deficits in a patient with central pontine myelinolysis following severe hyponatremia. Jpn J Med 1991;30:281–4. 23. Oh MS, Kim HJ, Carroll HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron 1995;70:143–50.
24. Sterns RH. The management of symptomatic hyponatremia. Semin Nephrol 1990;10:503–14. 25. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 2004;75:iii22–8.
doi:10.1016/j.jocn.2006.02.015
Terminal syringomyelia communicating with a spinal dermal sinus Natarajan Muthukumar
*
Department of Neurosurgery, Madurai Medical College, Madurai, India Received 25 November 2005; accepted 22 February 2006
Abstract Terminal syringomyelia occurs in approximately 25% of patients with occult spinal dysraphism. Congenital spinal dermal sinus is an uncommon form of occult spinal dysraphism. This case report highlights the rare association of terminal syringomyelia communicating with a spinal dermal sinus, resulting in an unique clinical presentation. The clinical, radiological and surgical findings of this unusual case are reported. 2006 Elsevier Ltd. All rights reserved. Keywords: Occult spinal dysraphism; Spinal dermal sinus; Terminal syringomyelia; Tight filum terminale
Terminal syringomyelia is a cystic dilatation of the lower third of the spinal cord.1 The reported incidence of terminal syringomyelia in occult spinal dysraphism varies from 24% to 27%.1,2 The common forms of occult spinal dysraphism that are associated with terminal syringomyelia are: tight filum terminale in the presence of an anorectal anomaly, meningocele manque´ and diastematomyelia, and is infrequently associated with other anomalies.1 The treatment of terminal syringomyelia associated with occult spinal dysraphism is controversial.1,2 Recent reports have documented progression of the terminal syrinx even after untethering of the cord.3,4 Spinal dermal sinus tracts are an uncommon form of occult spinal dysraphism often presenting in childhood with cutaneous findings, neurological deficits or infection.5 The true incidence of spinal dermal sinus tracts is not known and they are believed to be uncommon.6 The present case report highlights a rare association of a terminal syrinx in a patient with tethered cord that communicated with a spinal dermal sinus, resulting in epi-
* Present address: Muruganagam, 138, Anna Nagar, Madurai, Tamil Nadu 625020, India. Tel.: +91 452 2534 638/2534 551; fax: +91 452 2531 056. E-mail addresses: [email protected], [email protected].
Fig. 1. Clinical photograph showing the skin tag in the lumbar region.
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
Osmotic demyelination syndromes: Central and extrapontine myelinolysis S. Huq a
a,b,*
, M. Wong
c,d
, H. Chan
c,d
, D. Crimmins
c,d
Department of Neurology, Gosford District Hospital and Royal North Shore Hospitals, Pacific Highway, St Leonards, NSW 2065, Australia b Department of Medicine, University of Sydney, Camperdown, NSW, Australia c Department of Neurology, Gosford District Hospital, Gosford, NSW, Australia d Departments of Neurology and Medicine, University of Newcastle, Callaghan, NSW, Australia Received 16 December 2005; accepted 21 February 2006
Abstract Osmotic demyelination syndromes are often progressive disorders, with clinical features ranging from a mild tremor or dysarthria to a progressive quadraparesis. Although rapid correction of serum sodium is known to be a potent causative factor, additional pathogenic factors exist, which appear critical in predisposing pontine and extrapontine glia to osmotic stress. Interestingly, several cases of osmotic demyelination have emerged where serum sodium was found to be within normal limits and minimal or no correction of a hypo or hypernatraemic state was implemented. We describe two cases – one of extra pontine and another of central-pontine myelinolysis, both of which have occurred in the context of relatively normal serum sodium. The first case illustrates the association of extrapontine myelinolysis with the traditional risk factor of alcoholic cirrhosis and intravenous fluid resuscitation, while the second, more unusual case, describes a patient who developed central pontine myelinolysis possibly in association with alpha interferon therapy. 2006 Elsevier Ltd. All rights reserved. Keywords: Central Pontine Myelinolysis; Chronic Liver Disease; Hyponatraemia; Alpha Interferon
1. Introduction Osmotic demyelination syndromes, which consist of central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM), are rapidly progressing, often fatal focal symmetric syndromes, with clinical features ranging from a mild tremor or dysarthria to a progressive quadraparesis and a locked-in syndrome. The aetiology of osmotic demyelination is not well understood. Although rapid correction of serum sodium in the context of chronic hyponatraemia has been implicated as a potent causative factor,1 it is clear now that additional pathogenic factors exist, which are critical in predisposing pontine and extrapontine glia to osmotic stress.2 Among these, the most prominent appear to be significant alcohol use and orthotopic liver transplantation.3,4 Interestingly, several cases of CPM and EPM have been described in the literature where serum sodium was found to be within normal limits.5 We describe two cases, one of extra pontine and another of central-pontine myelinolysis, both of which have occurred in the presence of chronic liver disease and normal serum sodium. The first case illustrates the association of extrapontine myelinolysis with the traditional risk factor of alcoholic cirrhosis and intravenous fluid resuscitation. The second, more unusual
*
Corresponding author. Tel.: +612 9926 8656; fax: +612 9439 8418. E-mail address: [email protected] (S. Huq).
case describes a patient with chronic liver disease secondary to viral hepatitis, who developed CPM with normal serum sodium levels, no correction of electrolyte status, and the possible additional risk factor of alpha interferon therapy. 1.1. Case 1 A 56-year-old man with known alcoholic liver disease was brought into the emergency department. He was unconscious on arrival and reported to have been drinking heavily. Vital signs were normal, and he was afebrile. On examination he was acutely delirious. Neurological examination revealed equal but sluggishly reactive pupils. He was hypertonic in both limbs, and his reflexes were brisk with bilaterally upgoing plantar responses. Power, coordination and sensation could not be formally assessed, but he was moving all limbs and withdrawing from pain. The remaining systemic examination was unremarkable. He was admitted to an intensive care unit (ICU) where high flow oxygen and intravenous fluids were administered. To investigate his poor level of consciousness, a urine drug screen and a septic work-up was performed, both of which were negative. His blood alcohol level was 2 mmol/L (0– 4.3 mmol/L). Blood glucose was measured at 5.1 mmol/L (3.5–8.0 mmol/L). A full blood count, electrolytes, urea and creatinine, calcium, magnesium and phosphate, thyroid function test and troponin were all within normal limits. Liver function tests were consistent with the history of
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
alcoholic cirrhosis, with an elevated bilirubin, alkaline phosphotase and gamma-glutamyl transferase. Serum sodium was 140 mmol/L (135–149 mmol/L) at presentation and remained within normal limits through the entire admission. Over the next 24 h, further management with intravenous thiamine and vitamin supplementation was implemented and his level of consciousness gradually improved. Ceftriaxone was started for possible sepsis, as well as intravenous phenytoin for seizure prophylaxis. Formal neurological testing subsequently revealed ataxia, dysdiadochokinesis, and poor coordination bilaterally. Given persisting signs, further investigations were performed to exclude a brainstem infarct, meningoencephalitis, subdural haematoma or hypoxic brain injury. Cranial CT scanning and a lumbar puncture were performed, both of which were normal. Finally, an MRI of the brain revealed multiple foci of hyper-intense long TR signals in the cerebral white matter, the corpus callosum and the cerebellar hemispheres bilaterally (Fig. 1a, b). However, there were no signal changes within the pons, and no loss of grey-white differentiation to suggest a hypoxic insult. These MRI findings were consistent with extra pontine myelinolysis. The patient had a fluctuating course of illness over the next 3 weeks and required high-level nursing care. By day 5 he was orientated to time and place, and speaking more fluently. His mental state gradually improved and he was finally discharged to a rehabilitation hospital on day 21 of admission. 1.2. Case 2 A 51-year-old man presented for assessment with a 4-week history of gradual onset of dysarthria, fine-move-
685
ment incoordination and unsteadiness of gait. These symptoms deteriorated during the day and improved after rest. His background history included hepatitis C infection (genotype 3a), acquired 15 years previously through intravenous drug use, and complicated by cirrhosis. His other medical history was significant for type 2 diabetes mellitus of 10 years duration, complicated by retinopathy and nephropathy. Two weeks prior to admission, he had just finished a 6-month course of alpha interferon treatment for the viral hepatitis. He reported being completely abstinent from alcohol for at least two years prior to commencement of this treatment. On examination, the patient was alert and orientated with normal vital signs. Neurological examination revealed normal tone but brisk reflexes, especially in the lower limbs. The power of the left leg was reduced to 4/5. Coordination was impaired on the left side with past pointing in the left hand and dysdiadochokinesis in the left leg. Sensory and cranial nerve examinations were unremarkable. He also had peripheral stigmata of chronic liver disease with ecchymoses, spider naevi, and tender hepato-splenomegaly. Given the above neurological findings, the diagnostic possibilities included a brainstem or cerebellar infarct or neoplasm, cerebellitis, multiple sclerosis or a late-onset hereditary ataxia. Laboratory tests showed a normal serum sodium level of 139 mmol/L (135–145 mmol/L). Serum sodium, which was checked quarterly while on alphainterferon therapy, had always been within normal limits prior to admission. Liver function tests revealed a transaminitis consistent with the history of chronic hepatitis. Alpha-foetal protein levels were normal. Neurological work-up including a lumbar puncture and cranial CT scan were normal. Magnetic resonance imaging demonstrated
Fig. 1. T2 axial (A) and FLAIR (B) MRI of cerebellum and brainstem (case 1). In the cerebellar hemispheres bilaterally, there are hyperintense long TR signal abnormalities (arrows) involving the white matter, fairly symmetrical and extending to the posterior margin of the middle cerebellar peduncles, particularly on the right side, consistent with extrapontine myelinolysis.
686
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
Fig. 2. T2 axial (A), and diffusion weighted (B) MRI of the cerebrum and pons (case 2). Symmetrically within the central pons there are hyperintense long TR signals sparing the periphery, without mass effect (arrows), consistent with central pontine myelinolysis.
hyperintense long TR signals within the central pons sparing the periphery (Fig. 2a, b). These MRI features were consistent with central pontine myelinolysis. No particular treatment apart from supportive measures was initiated. The patient was reviewed regularly on a clinical basis as an outpatient. He remains well at 1-month follow-up, although the majority of his neurological findings persist. 2. Discussion Advances in neuroimaging, especially MRI, have allowed earlier detection of the characteristic lesions of CPM and EPM. The prevalence of this condition, once thought to be rare, is highlighted by a number of large series, with one demonstrating an incidence of 3/1000 in an unselected urban hospital population group.6 Evidence from clinical and laboratory data implicate hyponatraemia as a potent risk factor predisposing to CPM,7–9 and rapid sodium replacement has been implicated as one of the principal pathogenic stimuli to glial damage.10 The precise mechanism by which cellular injury occurs in CPM/EPM is speculative and the prevailing hypothesis implicates reduced adaptive capacity of neuroglia to large shifts in serum osmolarity.11,12 Critical discrepancies to this hypothesis are that most patients receiving even rapid sodium correction do not develop CPM.2 Conversely, mildly hyponatraemic patients whose rate of replacement never exceeded 11 mmol/24 h can develop CPM.13,14 A background predisposition thus appears to be central to the development of this clearly heterogeneous condition. Two conditions appear to be particular risk factors for the development of CPM/EPM. These include chronic alcohol abuse and
orthotopic liver transplantation.3,4 The latter group is particularly predisposed to CPM by virtue of operative and post-operative fluid resuscitation, co-existent renal disease and electrolyte derangement, and the use of cyclosporin A.4 Pathologically, CPM/EPM has been characterised by dissolution of the myelin sheaths and sparing of nerve axons within the central aspect of the basis pontis or extrapontine regions. Surprisingly, given the extent of glial cell death, there is a conspicuous absence of scavenger cells or inflammatory response, leading to the suggestion that cell death is mediated largely by apoptosis.15 Glial cells, the vulnerable cells in CPM, play a critical role in regulating extracellular osmolality and electrolyte balance in support of the neurones they envelop. In the face of an osmotic challenge, neuroglia activate energy-dependant cell surface pumps (eg. Na-K ATPase) to rapidly counteract the electrolyte derangement.2 In patients with liver failure, it is postulated that glia may inherently lack a plentiful supply of glucose or glycogen, hence relatively minor osmotic derangements lead to rapid depletion of cellular energy supply and cell death.2 This certainly appears to be the case with the two cases we describe, where despite a relatively normal serum sodium, both patients developed extensive demyelination. The second case is particularly interesting in this respect, as the patient developed CPM in the outpatient setting, in the absence of fluid resuscitation and relatively normal serum sodium. An increasing number of risk factors are being recognised for the development of osmotic demyelination, including adrenal insufficiency, malnutrition, chronic renal failure and haemodialysis, sepsis, and malignancy.2 As such, with more than one predisposing factor, CPM may
Case reports / Journal of Clinical Neuroscience 14 (2007) 684–688
indeed develop in the absence of serum sodium fluctations. Case 2 clearly demonstrates this, where the patient had both liver disease and diabetic nephropathy. Furthermore, he underwent treatment with alpha-interferon. Alphainterferon has been associated with a number of adverse neuropsychiatric effects, including paraesthesia,16 seizure activity,16 depression, neuralgic amyotrophy and polyradiculopathy,17 and severe neuropathy.18 Given the above, we hypothesise that this patient may well have developed CPM as a result of a combination of events, where chronic liver disease and renal insufficiency acted as predisposing factors and the addition of a biological modulator lead to glial injury. To our knowledge, the association of interferon treatment with osmotic demyelinating syndromes has not been previously described. It is interesting to note that the patient developed CPM several months after commencement of interferon therapy. With the extensive use of alpha-interferon, adverse effects are increasingly being recognised as early-onset (within 3 months of therapy) such as depression and influenza-like symptoms, and lateonset (after 3 months), such as anterior ischaemic optic neuropathy and myasthenia gravis and sarcoidosis.19 Indeed, Finsterer et al.20 reported a case of multifocal leukoencephalopathy and sensory-motor polyneuropathy 16 years after the commencement of alpha-interferon therapy. We hypothesise that CPM might be a late-onset adverse event of alpha-interferon therapy, hence the development of symptoms several months after initiation of therapy. Prognostically, the osmotic demyelinating syndromes are highly heterogenous with complete recovery and reversal of MRI findings reported in some cases to progression and death in others. No specific treatment has been shown to convincingly halt the progress or reverse CPM/EPM. Although isolated case reports suggest that steroids21 or thyrotropin releasing hormone22 may be helpful, no randomised trials exist. A number of guidelines outlining the appropriate rate of sodium replacement in a hyponatraemic patient have been published;23,24 however, there is a distinct paucity of recommendations relating to the management of individuals with normal serum sodium at presentation. To date, prevention of osmotic demyelination remains the mainstay of treatment. The predominant view (arising largely from case studies)25 is that in individuals with one or more risk factors (severe systemic illness, alcoholism, liver transplantation, or malnutrition) should undergo frequent neurological assessment coupled with appropriate imaging (MRI vs. CT) to make the diagnosis. CPM/EPM needs to be particularly considered in individuals who fail to recover as expected after severe illness or in patients manifesting new ‘‘psychiatric symptoms’’ after severe illness.25 It is recommended that high-risk individuals, once identified, should receive prompt treatment with nutritional supplements, with exacerbating factors such as drugs and salt-losing nephropathies corrected.2 Finally, a multi-disciplinary neuro-rehabilitation program combined with symptomatic
687
treatment of any movement disorders (which sometimes accompany EPM) should be implemented to promote a complete functional recovery.
References 1. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hitherto undescribed disease occurring in alcoholic and malnourished patients. Arch Neurol Psychiatry 1959;81:154–72. 2. Ashrafian H, Davey P. A review of the causes of central pontine myelinosis: yet another apoptotic illness? Eur J Neurol 2001;8: 103–9. 3. Singh N, Yu VL, Gayowski T. Central nervous system lesions in adult liver transplant recipients: clinical review with implications for management. Medicine (Baltimore) 1994;73:110–8. 4. Yu J, Zheng SS, Liang TB, et al. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004;10:2540–3. 5. Mast H, Gordon PH, Mohr JP, et al. Central pontine myelinolysis: clinical syndrome with normal serum sodium. Eur J Med Res 1995;1: 168–70. 6. Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain 1979;102:361–85. 7. Victor M, Laureno R. Neurologic complications of alcohol abuse: epidemiologic aspects. Adv Neurol 1978;19:603–17. 8. Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats. Kidney Int 1988;34:351–60. 9. Verbalis JG, Martinez AJ. Neurological and neuropathological sequelae of correction of chronic hyponatremia. Kidney Int 1991;39: 1274–82. 10. Kleinschmidt-DeMasters BK, Norenberg MD. Neuropathologic observations in electrolyte-induced myelinolysis in the rat. J Neuropathol Exp Neurol 1982;41:67–80. 11. Sterns RH, Thomas DJ, Herndon RM. Brain dehydration and neurologic deterioration after rapid correction of hyponatremia. Kidney Int 1989;35:69–75. 12. Verbalis JG, Gullans SR. Rapid correction of hyponatremia produces differential effects on brain osmolyte and electrolyte reaccumulation in rats. Brain Res 1993;606:19–27. 13. Riggs JE, Schochet Jr SS. Osmotic stress, osmotic myelinolysis, and oligodendrocyte topography. Arch Pathol Lab Med 1989;113: 1386–8. 14. Sterns RH, Baer J, Ebersol S, et al. Organic osmolytes in acute hyponatremia. Am J Physiol 1993;264:F833–6. 15. Newell KL, Kleinschmidt-DeMasters BK. Central pontine myelinolysis at autopsy; a twelve year retrospective analysis. J Neurol Sci 1996;142:134–9. 16. Smedley H, Katrak M, Sikora K, et al. Neurological effects of recombinant human interferon. Br Med J (Clin Res Ed) 1983;286: 262–4. 17. Adams F, Quesada JR, Gutterman JU. Neuropsychiatric manifestations of human leukocyte interferon therapy in patients with cancer. JAMA 1984;252:938–41. 18. Bernsen PL, Wong-Chung RE, Janssen JT. Neuralgic amyotrophy and polyradiculopathy during interferon therapy. Lancet 1985;1 (8419):50. 19. Kreutzer K, Bonnekoh B, Franke I, et al. [Sarcoidosis, myasthenia gravis and anterior ischaemic optic neuropathy: severe side effects of adjuvant interferon-alpha-therapy in malignant melanoma?]. J Dtsch Dermatol Ges 2004;2:689–94. 20. Finsterer J, Sommer O, Stiskal M. Multifocal leukoencephalopathy and polyneuropathy after 18 years on interferon alpha. Leuk Lymphoma 2005;46:277–80. 21. Nishino K, Yasuda T, Kowada M. [A case of central pontine myelinolysis with neurological recovery after administration of gluco corticoid]. No To Shinkei 1991;43:483–8.
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22. Wakui H, Nishimura S, Watahiki Y, et al. Dramatic recovery from neurological deficits in a patient with central pontine myelinolysis following severe hyponatremia. Jpn J Med 1991;30:281–4. 23. Oh MS, Kim HJ, Carroll HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron 1995;70:143–50.
24. Sterns RH. The management of symptomatic hyponatremia. Semin Nephrol 1990;10:503–14. 25. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry 2004;75:iii22–8.
doi:10.1016/j.jocn.2006.02.015
Terminal syringomyelia communicating with a spinal dermal sinus Natarajan Muthukumar
*
Department of Neurosurgery, Madurai Medical College, Madurai, India Received 25 November 2005; accepted 22 February 2006
Abstract Terminal syringomyelia occurs in approximately 25% of patients with occult spinal dysraphism. Congenital spinal dermal sinus is an uncommon form of occult spinal dysraphism. This case report highlights the rare association of terminal syringomyelia communicating with a spinal dermal sinus, resulting in an unique clinical presentation. The clinical, radiological and surgical findings of this unusual case are reported. 2006 Elsevier Ltd. All rights reserved. Keywords: Occult spinal dysraphism; Spinal dermal sinus; Terminal syringomyelia; Tight filum terminale
Terminal syringomyelia is a cystic dilatation of the lower third of the spinal cord.1 The reported incidence of terminal syringomyelia in occult spinal dysraphism varies from 24% to 27%.1,2 The common forms of occult spinal dysraphism that are associated with terminal syringomyelia are: tight filum terminale in the presence of an anorectal anomaly, meningocele manque´ and diastematomyelia, and is infrequently associated with other anomalies.1 The treatment of terminal syringomyelia associated with occult spinal dysraphism is controversial.1,2 Recent reports have documented progression of the terminal syrinx even after untethering of the cord.3,4 Spinal dermal sinus tracts are an uncommon form of occult spinal dysraphism often presenting in childhood with cutaneous findings, neurological deficits or infection.5 The true incidence of spinal dermal sinus tracts is not known and they are believed to be uncommon.6 The present case report highlights a rare association of a terminal syrinx in a patient with tethered cord that communicated with a spinal dermal sinus, resulting in epi-
* Present address: Muruganagam, 138, Anna Nagar, Madurai, Tamil Nadu 625020, India. Tel.: +91 452 2534 638/2534 551; fax: +91 452 2531 056. E-mail addresses: [email protected], [email protected].
Fig. 1. Clinical photograph showing the skin tag in the lumbar region.