My patient on chronic oral baclofen began having mental status changes and hallucinations soon after hospitalization while still receiving baclofen. Could a lower than home-dose of baclofen have caused his withdrawal symptoms?

Absolutely! Although we usually think of withdrawal symptoms in the setting of complete discontinuation of certain CNS depressants, even a reduced dose of baclofen1,2 in a patient who has been on a higher dose chronically can precipitate full-blown withdrawal symptoms, such as delirium, fevers, hallucinations, hyperspasticity, autonomic instability and even respiratory failure, multiorgan failure, cardiac arrest and death.1-5

Recall that baclofen is a GABA-B agonist and a potent inhibitor of neuronal synapses with resultant decreased excitation of muscle spindles and muscle spasticity.6 Similar to other benzodiazepines, baclofen is also a CNS depressant and bears many similarities with alcohol in its physiologic effects.  For example, baclofen and alcohol both produce unsteady gait, dizziness, mood alterations and impairment in attention and memory and reduce anxiety, among others.  Not surprisingly, abrupt withdrawal from baclofen may produce similar symptoms as those associated with alcohol withdrawal, such as confusion, hallucination and delirium (observed in our patient) as well as seizures.3 Withdrawal symptoms typically occur 24-48 hours after discontinuation or reduction in the dose of baclofen.1,2

Of course, many of our hospitalized patients are already at risk of mental status changes or sedation from their underlying conditions or from medications needed to treat them.  In this setting, consideration in reducing the home dose of certain CNS depressants, such as baclofen, is understandable and reasonable. However, we should also keep in mind that even a reduction in the chronic dose of baclofen carries a risk of withdrawal!  Unfortunately, healthcare facilities often lack established management protocols for anticipated interruption of oral baclofen.7

In our patient, the home dose of baclofen had been reduced by one-half following his admission. Worsening delirium and new onset visual and auditory hallucinations were noted within a few days of hospitalization. Thankfully, no further bouts of confusion or hallucination was observed after resuming his home dose.

Bonus Pearl:

Did you know that baclofen is often used (off label) to treat intractable hiccups of central origin? 8,9

Contributed by Fahad Tahir, MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Terrence CF, Fromm GH. Complications of Baclofen Withdrawal. Arch Neurol. 1981;38(9):588–589. doi:10.1001/archneur.1981.00510090082011. https://jamanetwork.com/journals/jamaneurology/article-abstract/580084
  1. O’Rourke, F., Steinberg, R., Ghosh, P., & Khan, S. (2001). Withdrawal of baclofen may cause acute confusion in elderly patients. BMJ (Clinical research ed.), 323(7317), 870.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121408/ 
  1. de Beaurepaire R. A review of the potential mechanisms of action of baclofen in alcohol use disorder. Front. Psychiatry 2018; 9:506). In fact, baclofen may be a promising treatment for alcohol use disorder. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232933/pdf/fpsyt-09-00506.pdf
  2. Cardoso AL, Quintaneiro C, Seabra H, Teixeira C. Cardiac arrest due to baclofen withdrawal syndrome. BMJ Case Rep. 2014;2014:bcr2014204322. Published 2014 May 14.doi:10.1136/bcr-2014-204322 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025399/pdf/bcr-2014-204322.pdf
  1. Green LB, Nelson VS. Death after acute withdrawal of intrathecal baclofen: case report and literature review. Arch Phys Med Rehabil. 1999 Dec;80(12):1600-4. doi: 10.1016/s0003-9993(99)90337-4. PMID: 10597813. https://www.archives-pmr.org/article/S0003-9993(99)90337-4/pdf
  1. Allerton CA, Boden PR, Hill RG. Actions of the GABAB agonist, (-)-baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro. Br J Pharmacol. 1989;96(1):29-38. doi:10.1111/j.1476-5381.1989.tb11780.x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1854300/
  1. Schmitz NS, Krach LE, Coles LD, Schrogie J, Cloyd JC, Kriel RL. Characterizing Baclofen Withdrawal: A National Survey of Physician Experience. Pediatr Neurol. 2021 Sep;122:106-109. doi: 10.1016/j.pediatrneurol.2021.06.007. Epub 2021 Jul 28. PMID: 34330615. https://www.pedneur.com/article/S0887-8994(21)00129-6/fulltext
  1. Zhang, C., Zhang, R., Zhang, S. et al. Baclofen for stroke patients with persistent hiccups: a randomized, double-blind, placebo-controlled trial. Trials 15, 295 (2014). https://doi.org/10.1186/1745-6215-15-295
  1. Jeon YS, Kearney AM, Baker PG Management of hiccups in palliative care patients BMJ Supportive & Palliative Care 2018;8:1-6. https://spcare.bmj.com/content/8/1/1.long

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My patient on chronic oral baclofen began having mental status changes and hallucinations soon after hospitalization while still receiving baclofen. Could a lower than home-dose of baclofen have caused his withdrawal symptoms?

Can Covid-19 exacerbate seizures in patients with epilepsy?

There have been several reports of seizure exacerbation in epileptic patients after Covid-19 infection. Seizure exacerbations have been observed in epileptic patients with uncontrolled epilepsy, as well as patients who were previously controlled with antiepileptic drugs (AEDs).1,2

In a survey of 362 epileptic patients in Wuhan, China, the site of the initial outbreak, 31 (8.6%) patients reported an increased number of seizures in the month after the public lockdown began; 16 (51.6%) of the 31 patients with seizure exacerbation had prior exposure to Covid-19.1

In a study of 439 patients with Covid-19 infection in Egypt, 19 (4.3%) patients presented with acute seizures.2  Two of the 19 seizure patients had a previous diagnosis of epilepsy, which had been controlled for up to 2 years. Interestingly, the other 17 patients had new onset seizures without a previous epilepsy diagnosis.

Covid-19 has been proposed to induce seizures by eliciting inflammatory cytokines in the central nervous system, leading to neuronal necrosis and increased glutamate levels in the cerebral cortex and hippocampus.3

Covid-19 infection may have also indirectly caused seizure exacerbations in a number of epileptic patients. Interestingly, stress related to worrying about the effect of the outbreak on a patient’s seizure activity was associated with seizure exacerbations (odds ratio: 2.5, 95% CI: 1.1-6.1)2. It is also possible that some seizure exacerbations may have been due to fear of visiting the hospital and AED withdrawal, as was demonstrated during the 2003 SARS outbreak.4

Bonus Pearl: Did you know that Guillain–Barré Syndrome has also been observed in patients with Covid-19 infection?5

Contributed by Luke Vest, Medical Student, St. Louis University Medical School

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References:

  1. Huang, S., Wu, C., Jia, Y., et al. (2020). COVID-19 outbreak: The impact of stress on seizures in patients with epilepsy. Epilepsia, 61(9), 1884-1893. https://doi.org/10.1111/epi.16635  
  2. Khedr, E. M., Shoyb, A., Mohammaden, M., & Saber, M. (2021). Acute symptomatic seizures and COVID-19: Hospital-based study. Epilepsy Res, 174, 106650. https://doi.org/10.1016/j.eplepsyres.2021.106650
  1. Nikbakht, F., Mohammadkhanizadeh, A., & Mohammadi, E. (2020). How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Multiple sclerosis and related disorders, 46, 102535. https://doi.org/10.1016/j.msard.2020.102535
  2. Lai, S. L., Hsu, M. T., & Chen, S. S. (2005). The impact of SARS on epilepsy: the experience of drug withdrawal in epileptic patients. Seizure, 14(8), 557–561. https://doi.org/10.1016/j.seizure.2005.08.010
  3.  Abu-Rumeileh, S., Abdelhak, A., Foschi, M., Tumani, H., & Otto, M. (2021). Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. Journal of neurology, 268(4), 1133–1170. https://doi.org/10.1007/s00415-020-10124-x   

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions, or St. Louis University Medical School. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Can Covid-19 exacerbate seizures in patients with epilepsy?

What is the connection between anosmia, anasognosia and Alzheimer’s disease?

Both anosmia (loss of smell) and anosognosia (lack of awareness or insight of a deficit) appear to be strongly associated with higher risk of development of Alzheimer’s Disease (AD).1,2

In a study involving 90 patients with mild cognitive impairment (MCI) followed for up to 2 years, subjects with low olfaction scores were significantly more likely to develop AD than those with high scores (40% vs 0%, p<0.001).  In the same study, all patients with anosognosia (accounting for 84% of the low olfaction group) developed AD irrespective of higher baseline Mini Mental State Examination (MMSE) score. 1

A 2017 meta-analysis of olfactory dysfunction in MCI also found a significant association between olfactory deficits and MCI with tests of odor identification having larger effect sizes than those of odor detection threshold or memory.2

As for possible mechanisms, anosmia in AD is felt to be due to degeneration of neurons of the entorhinal- hippocampal-subicular complex associated with an observed increase in neurofibrillary tangles.3 Interestingly, the density of tau tangles in the entorhinal cortex have been shown to be inversely related to odor identification.4  There also seems to be a correlation between anosognosia and atrophy in the dorsal anterior cingulate cortex, reflected by the finding of hypometabolism on PET-FDG images6.

Bonus Pearl: Did you know that anosmia and ageusia (loss of sense of taste) are also common nonmotor feature of Parkinson’s Disease and can predate onset of motor symptoms by years? 5

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References

  1. Devanand DP, Michaels-Marston KD, Liu X, et al: Olfactory Deficits in Patients With Mild Cognitive Impairment Predict Alzheimer’s Disease at Follow-Up. Am J Psychiatry, 2000; 157:1399-405 https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.157.9.1399                                   
  2. Roalf DR, Moberg MJ, Turetsky BI, et al: A quantitavie meta-analysis of olfactory dysfunction in mild cognitive impairment. J Neurology Neurosurg Psychiatry 2017;88:226-232. https://jnnp.bmj.com/content/88/3/226
  3. Talamo BR, Rudel R, Kosik KS, et al: Pathological changes in olfactory neurons in patients with Alzheimer’s disease. Nature 1989; 337:736–739. https://doi.org/10.1038/337736a0 
  4. Wilson RS, Arnold, SE, Schneider JA, et al: The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry, 2007;78:30-5. https://doi.org/10.1136/jnnp.2006.099721
  5. Tarakad A, Jankovic J: Anosmia and Ageusia in Parkinson’s Disease. International Review of Neurobiology, 2017; 133:541-556https://doi.org/10.1016/bs.irn.2017.05.028
  6. Guerrier L, Le Men J, Gain, A, et al: Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer’s Disease Patients. Journal of Alzheimer’s Disease 2018; 65:443-453. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180324

Contributed by Jackie Fairchild MD, Mercy Hospital-St. Louis, St. Louis, Missouri

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy, its affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What is the connection between anosmia, anasognosia and Alzheimer’s disease?

What’s the connection between dialysis and cognitive impairment in patients with chronic kidney disease (CKD)?

Cognitive impairment (CI) is extremely common among dialysis patients affecting  up to ~70% or more  of patients (1-3).   Pre-existing conditions, dialysis process itself and uremic, metabolic and vascular disturbances associated with end stage renal failure may all contribute to the CI in patients on dialysis (1-5).

Among pre-existing conditions, vascular disease is considered the major contributing factor to the risk of CI in dialysis patients (3). The prevalence of stroke is very high among hemodialysis (HD) ( ~15%) and CKD patients (~10%) compared to non-CKD patients (~2%).  History of stroke also doubles the risk of dementia in both the non-CKD and HD patients. Subclinical cerebrovascular disease due to silent strokes and white matter disease —common in CKD and dialysis patients—are also associated with increased risk of cognitive and physical decline and incident dementia.  White matter disease is thought to be related to microvascular disease and chronic hypoperfusion (1).

Dialysis itself may be associated with acute confusional state due to cerebral edema caused by  acute fluid, urea, and electrolyte shifts during dialysis (particularly among newly initiated HD patients).  Some have suggested that the optimal cognitive function in HD patients is around 24 h after HD (1).

Chronic rapid fluctuations in blood pressure, removal of large fluid volumes and hemoconcentrations can further increase the risk of cerebral hypoperfusion, potentially accelerating vascular cognitive impairment in HD patients (1).

 Bonus Pearl: Did you know that while cerebral ischemia (measured by PET-CT or other non-invasive means) is common during HD, it may occur in the absence of intra-dialysis hypotension (6,7)?

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References

  1. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis 2008;15:123-32. https://www.ackdjournal.org/article/S1548-5595(08)00011-6/pdf
  2. Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006;67:216-223. https://experts.umn.edu/en/publications/cognitive-impairment-in-hemodialysis-patients-is-common
  3. Van Zwieten A, Wong G, Ruospo M, et al. Prevalence and patterns of cognitive impairment in adult hemodialysis patients: the COGNITIVE-HD study. Nephrol Dial Transplant 208;33:1197-1206. https://pubmed.ncbi.nlm.nih.gov/29186522/
  4. Seliger SL, Weiner DE. Cognitive impairment in dialysis patients: focus on the blood vessels? Am J Kidney Dis 2013;61:187-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433757/
  5. Findlay MD, Dawaon J, Dickie DA, et al. Investigating the relationship between cerebral blood flow and cognitive function in hemodialysis patients. J Am Soc Nephrol 30:147-58. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317612/
  6. Polinder-Bos HA, Garcia DV, Kuipers J, et al. Hemodiaysis induces an acute decline in cerebral blood flow in elderly patients. J Am Soc Nephrol 208;29:1317-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875962/
  7. MacEwen C, Sutherland S, Daly J, et al. Relationship between hypotension and cerebral ischemia during hemodialysis. J Am Soc Nephrol 2017;38:2511-20. https://www.researchgate.net/publication/314298128_Relationship_between_Hypotension_and_Cerebral_Ischemia_during_Hemodialysis

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the connection between dialysis and cognitive impairment in patients with chronic kidney disease (CKD)?

How common are neurological symptoms in patients with Covid-19 infection?

Although we usually think of it as primarily a respiratory tract disease, neurological manifestations with Covid-19 are not at all uncommon,1-6 occurring in over one-third of hospitalized patients with Covid-19 according to one medRxiv report.1

In a Chinese study1 involving 214 hospitalized patients with Covid-19, 36.4% had 1 or more neurological symptoms, with the majority involving the central nervous system (CNS) (25.0%), of which the most common complaints were dizziness (17%) and headache (13.0%). Some patients (9.0%) had cranial nerve/peripheral nerve complaints of which the most common were difficulty with taste (hypogeusia) (6.0%) and sense of smell (hyposmia) (5.0%).  A fewer number of patients had impaired consciousness, acute cerebrovascular disease (including ischemic stroke and cerebral hemorrhage). Although not strictly-speaking a neurological manifestation, the study also reported “muscle injury” in ~20.0% of patients     (defined as myalgia plus CK >200 IU/L).

Descriptions of Covid-19 encephalopathy, including one associated with acute hemorrhagic necrotizing process, are also beginning to appear in the literature.3-5 Reports of “Neuro-Covid-19 units” in Italy further underlines the common occurrence of neurological symptoms in these patients.6

More than one mechanism for neurological complications in Covid-19 are likely,  including:1-2

  1. Direct viral invasion into the CNS which could explain the associated headache, high fever, vomiting, convulsions, and consciousness disorders. Some have reported normal CSF parameters but a report of PCR positive CSF suggests direct injury from the virus itself.2 Covid-19 virus may gain access to the CNS through direct invasion of neuronal pathways (eg. olfactory nerve given recent reports of difficulty with sense of smell) or through blood circulation.
  2. Indirect CNS injury through extreme systemic derangements such as hypoxia, or immune/inflammatory response-related injury (eg, through cytokines, hypercoagulability related to infection). Some have also posited that binding of Covid-19 virus to ACE2 may cause abnormally elevated blood pressure and increase the risk of cerebral hemorrhage.2

The fact that Covid-19 is so versatile and affects the nervous system as well shouldn’t surprise us. Neurological complications have been reported with couple of other related respiratory Coronaviruses such as those of SARS and MERS.2

 

Bonus pearl: Did you know that as early 1970-80s some coronaviruses were shown to cause “nasoencephalopathy” when injected intranasally in mice with subsequent spread to the CNS through the olfactory nerve?7 Maybe we shouldn’t be too surprised that sense of smell is impaired in some Covid-19 patients. If we could only stop the virus at the nose!

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References

  1. Mao L, Wang M, Chen S, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study. https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1
  2. Wu Y, Xu X, Chen Z, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity 2020, March 30. https://www.sciencedirect.com/science/article/pii/S0889159120303573
  3. Xiang et al. 2020. First case of 2019 novel Coronavirus disease with encephalitis. ChinaXiv, T202003 (2020), p. 00015 (obtained from reference 2).
  4. Poyiadji N, Shain G, Noujaim D, et al. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020 https://pubs.rsna.org/doi/10.1148/radiol.2020201187
  5. Filatov A, Sharma P, Hindi F, et al. Neurological complications of coronavirus (COVID-19): encephalopathy. Cureus 12(3): e7352. DOI 10.7759/cureus.7352 https://www.cureus.com/articles/29414-neurological-complications-of-coronavirus-disease-covid-19-encephalopathy
  6. Talan J. COVID-19: Neurologists in Italy to Colleagues in US: Look for poorly-defined neurologic conditions in patients with the Coronavirus. Neurology Today 2020, March 27. https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920
  7. Perlman S, Jacobsen G, Afifi A. Spread of a neurotropic murine Coronavirus into the CNS via the trigeminal and olfactory nerves. Virology 1989;170:556-560 https://www.sciencedirect.com/science/article/pii/0042682289904467

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

How common are neurological symptoms in patients with Covid-19 infection?

My patient with peripheral neuropathy was just diagnosed with monoclonal gammopathy of unclear significance (MGUS). Can these two conditions be related?

The presence of MGUS in patients with peripheral neuropathy (PN) may be either coincidental or causal. Younger age group (<50 y) and the presence of IgM MGUS increase the likelihood of a causal relationship between MGUS and peripheral neuropathy. 1

The likelihood of a causal relationship is higher in the younger age group because of the very low prevalence of M proteins (less than 1.5%) in this population making coincidental presence of MGUS and PN much less likely. In contrast, this relationship may just be coincidental in older patients because of higher baseline prevalence of MGUS (7% in those over 70 y old). 1  

Similarly, a causal relationship between MGUS and PN may be more likely when the M protein is IgM (vs IgG or IgA). In a study of patients with MGUS and peripheral neuropathy,  31% of patients with IgM MGUS had neuropathy vs 14% for IgA and 6% for IgG MGUS. In fact, among patients with PN without an obvious cause, the prevalence of an M protein may be as high as 10%.2  Whether the relationship between non-IgM MGUS and PN is causal remains unclear.3

Although the exact mechanism of MGUS-related PN is not known, pathologic studies in Waldenstrom macroglobulinemia and multiple myeloma have demonstrated demyelination and widened myelin lamellae associated with monoclonal IgM deposits.1

But before you implicate MGUS as the cause of PN, make sure to exclude common causes of PN, such as diabetes mellitus, alcoholism and potential drugs.

 

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References

  1. Chaudhry HM, Mauermann ML, Rajkumar SV. Monoclonal gammopathy—associated peripheral neuropathy: diagnosis and management. Mayo Clin Proc 2017; 92:838-50. https://www.mayoclinicproceedings.org/article/S0025-6196(17)30118-0/pdf
  2. Kelly JJ Jr, Kyle RA, O’Brien PC, et al. Prevalence of monoclonal protein in peripheral neuropathy. Neurology 1981;31:1480-83. https://www.ncbi.nlm.nih.gov/pubmed/6273767
  3. Nobile-Orazio E, Barbien L, Baldini L, et al. Peripheral neuropathy in monoclonal gammopathy of undetermined significance: prevalence and immunopathogenetic studies. Acta neurol Scand 1992;85:383-90. https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.1992.tb06033.x
My patient with peripheral neuropathy was just diagnosed with monoclonal gammopathy of unclear significance (MGUS). Can these two conditions be related?

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

Although there is often an overlap between the clinical presentation of serotonin syndrome (SS) and neuromuscular malignant syndrome (NMS), start out with the physical exam. The presence of hyperreflexia, tremors, clonus, hyperactive bowel sounds, and dilated pupils should make you think of SS, whereas hyporeflexia, “lead-pipe” rigidity in all muscle groups, normal pupils, and normal or decreased bowels sounds suggest NMS in the proper context.1-3 The most sensitive and specific sign of SS is clonus.1

Aside from physical exam findings, symptom onset in relation to the implicated drug may also be important. Onset of symptoms within 12-24 h of the initiation or change of an implicated drug suggests SS, whereas a more delayed onset (often 1-3 days) is more supportive of NMS.1-3  SS also tends to resolve within a few days after discontinuation of the offending agent, while NMS usually takes 9-14 days to resolve. 1-3 Although both SS and NMS can be associated with leukocytosis, elevated CK and low serum iron levels are more common in NMS.2

SS is caused by excess serotonin due to a variety of mechanisms—therefore medications— including inhibition of serotonin uptake ( eg, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, metoclopramide, ondansetron), inhibition of serotonin metabolism (seen with monoamine oxidase inhibitors , including linezolid, methylene blue), increased serotonin release (eg stimulants, including amphetamines, cocaine), and activation of serotonin receptors (eg, lithium), among others. 2

As for medications that can cause NMS, look for neuroleptic agents (eg, haloperidol, olanzapine, quetiapine, risperidone), as well as antiemeics, such as metoclopramide and promethazine.2

 

Bonus Pearl: Did you know that several supplements/herbal products have been associated with serotonin syndrome, including L-tryptophan, St. John’s wort and ginseng?1

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References

  1. Bienvenu OJ, Neufeld K, Needham DM. Treatment of four psychiatric emergencies in the intensive care unit. Crit Care Med 2012;40: 2662-70. https://insights.ovid.com/crossref?an=00003246-201209000-00017
  2. Turner AAH, Kim JJ, McCarron RM, et al. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry 2019;18: 36. https://www.mdedge.com/psychiatry/article/193418/schizophrenia-other-psychotic-disorders/differentiating-serotonin-syndrome
  3. Dosi R, Ambaliya A, Joshi H, et al. Serotonin syndrome versus neuroleptic malignant syndrome: a challenging clinical quandary. BMJ Case Rep 2014. Doi:10.1136/bcr-2014-204154. https://casereports.bmj.com/content/2014/bcr-2014-204154

 

How can I distinguish serotonin syndrome from neuroleptic malignant syndrome in my patient with fever and mental status changes?

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

Optimal timing of resumption of therapeutic anticoagulation (AC) in patients with hemorrhagic stroke or intracranial hemorrhage (ICH) is unclear because of lack of randomized controlled trials, but existing evidence suggests that 4-8 weeks may be reasonable in our patient (1). 
The American Heart Association/American Stroke Association 2015 guidelines recommend avoiding AC for at least 4 weeks in patients without mechanical heart valves (class IIB-very weak), while 1 study reported that prediction models of ICH in atrial fibrillation at high risk of thromboembolic event suggest that resumption of AC at 7-8 weeks may be the “sweet spot” when weighing safety against efficacy of AC in this patient population (1-3).
Two meta-analyses (1 involving patients with non-lobar ICH, another ICH in patients with nonvalvular atrial fibrillation) found that resumption of AC ranging from 10 to 44 days following ICH may be associated with decrease rates of thromboembolic events without significant change in the rate of repeat ICH (4,5).
There are many limitations to the published literature including their retrospective nature, unreported location and size of ICH in many studies, and use of warfarin (not DOACs) as an AC agent (1).
Clearly we need randomized controlled trials to answer this important question. In the meantime, a heavy dose of clinical judgement on a case-by-case basis seems appropriate.

Bonus Pearl: Did you know that lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) usually due to hypertensive vessel disease (1)? 

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References
1. Gibson D et al. When is it safe to resume anticoagulation in my patient with hemorrhagic stroke. The Hospitalist, February 5, 2019. https://www.the-hospitalist.org/hospitalist/article/193924/neurology/when-it-safe-resume-anticoagulation-my-patient-hemorrhagic/page/0/1
2. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60. https://www.ahajournals.org/doi/pdf/10.1161/STR.0000000000000069
3. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20 https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.116.014643
4. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600. https://www.ahajournals.org/doi/full/10.1161/strokeaha.116.016327
5. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730065/

When can I resume anticoagulation in my patient with atrial fibrillation and hemorrhagic stroke?

My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

Although originally described in 1949 in patients with liver disease and labelled as “liver flap”, numerous other causes of asterixis exist aside from severe liver disease (1,2). As early as 1950s, asterixis was observed among some patients with heart failure and pulmonary insufficiency but without known significant liver disease (3). Azotemia has also been associated with asterixis.

 
Don’t forget about medication-associated asterixis . Commonly used drugs such as gabapentin, pregabalin, phenytoin, and metoclopramide have been associated with asterixis (1,4) . Even antibiotics such as ceftazidime and high dose trimethoprim-sulfamethoxazole may be culprits (1,5). There are many psychiatric drugs including lithium, carbamazepine, clozapine, and valproic acid that have been implicated (1,6) as well. Some reviews have also included hypomagnesemia and hypokalemia on the list of causes of asterixis (1).

 
Although asterixis is essentially a negative myoclonus with episodic loss of electrical activity of muscle and its tone, its exact pathophysiology remains unclear (7). 

 

Bonus Pearl: Did you know that the origin of the word asterixis is An (negative)-iso (equal)-sterixis (solidity) which was shortened by Foley and Adams, its original discoverers, to what we now refer to as “asterixis” (1).

 

References
1. Agarwal R, Baid R. Asterixis. J Postgrad Med 1016;62:115-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944342/ 2. Pal G, Lin MM, Laureno R. Asterixis: a study of 103 patients. Metab Brain Dis; 2014:29:813-24. https://link.springer.com/article/10.1007%2Fs11011-014-9514-7
3. Conn HO. Aterixis—Its occurrence in chronic pulmonary disease, with a commentary on its general mechanism. N Engl J Med 1958;259:564-569. https://www.nejm.org/doi/full/10.1056/NEJM195809182591203
4. Kim JB, Jung JM, Park MH. Negative myoclonus induced by gabapentin and pregabalin: a case series and systemic literature review. J Neurol Sci 2017;382:36-9. https://www.sciencedirect.com/science/article/pii/S096758681830225X
5. Gray DA, Foo D. Reversible myoclonus, asterixis, and tremor associated with high dose trimethoprim-sulfamethoxazole: a case report. J Spinal Cord Med 2016; Vol. 39 (1), pp. 115-7. https://www.ncbi.nlm.nih.gov/pubmed/26111222
6. Nayak R, Pandurangi A, Bhogale G, et al. Aterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. J Neuropsychiatry Clin Neurosci 2012;24: E26-7. https://neuro.psychiatryonline.org/doi/pdf/10.1176/appi.neuropsych.101102667. Ugawa Y, Shimpo T, Mannen T. Physiological analysis of asterixis: silent period locked averaging. J Neurol Neurosurg Psych 1989;52:89-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032663/pdf/jnnpsyc00523-0104.pdf

 

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My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?

Consider strychnine poisoning as a cause of recurrent generalized tonic clonic seizures and muscle spasm with clear sensorium either during or following the episode. 1-4 In contrast to the cortical source of most seizures, convulsions due to strychnine poisoning are due to the blocking of the action of spinal and brain-stem inhibitory neurons resulting in overwhelming muscle rigidity, not unlike that seen in tetanus.

Although strychnine was found in various tonics and cathartic agents and was a common cause of accidental death in children under 5 years of age in early 20th century, it is still used in various rodenticides and pesticides.3  Today, it may be used intentionally in suicide attempts as well as an adulterant in street drugs, such as amphetamines, heroin and especially cocaine. 1,3,5

The initial symptoms of strychnine poisoning include nervousness, a hyperalert state, and confusion. These symptoms may be followed by severe muscle rigidity throughout the body often in response to minimal stimuli, such as physical contact, bright lights, noise and medical procedures.3, 6,7  Interestingly, strychnine also has an excitatory action on the medulla and enhances the sensation of touch, smell, hearing and sight.6  The cause of death is usually respiratory arrest due to prolonged muscle spasms, often complicated by rhabdomyolysis and associated renal failure.1

So among the numerous causes of seizures, think of strychnine as another potential cause when there is no concurrent loss of consciousness or the expected postictal state.

Bonus Pearl: Did you know that strychnine may be present in street drugs with a variety of names such as “back breakers”, “homicide”, “red rock opium”, “red stuff” and “spike”? 7

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References

  1. Wood DM, Webser E, Martinez D, et al. Case report: survival after deliberate strychnine self-poisoning, with toxicokinetic data. Critical Care 2002;6:456-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC130147/
  2. Santhosh GJ, Joseph W, Thomas M. Strychnine poisoning. J Assoc Physicians India 2003;51:736. https://www.ncbi.nlm.nih.gov/pubmed/14621058
  3. Libenson MH, Young JM. Case records of Massachusetts General Hospital. A 16 years boy with an altered mental status and muscle rigidity. N Engl J Med 2001;344:1232-9. https://www.nejm.org/doi/full/10.1056/NEJM200104193441608
  4. Smith BA. Strychnine poisoning. J Emerg Med 1990;8: 321-25. https://www.ncbi.nlm.nih.gov/pubmed/2197324
  5. O’Callaghan WG, Ward M, Lavelle P, et al. Unusual strychnine poisoning and its treatment: report of eight cases. B Med J 1982;285:478. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1499293/
  6. Burn DJ, Tomson CRV, Seviour J, et al. Strychnine poisoning as an unusual cause of convulsions. Postgrad Med J 1989;65:563-64. https://www.ncbi.nlm.nih.gov/pubmed/2602253
  7. Radosavljevic J, Jeffries WS, Peter JV. Intentional strychnine use and overdose—an entity of the past? Crit Care Resusc 2006;8: 260-61. https://www.ncbi.nlm.nih.gov/pubmed/16930120

 

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?