Syllabus Pharmaceuticals Related Neurotoxicity C16 Kumar April 22 Sat 2023 AAN

April 22, 2023 (Saturday)
12.15 pm – 2.15 pm
Neurologic Complications of Other Pharmaceuticals

1.25 pm – 2.00 pm
Neeraj Kumar, MD
Department of Neurology, Mayo Clinic,
Rochester, MN
Off label usage: Financial Relationship(s):

None None
Objectives:
Be aware of neurologic toxicities related to

pharmaceuticals and recognize common drug-induced
toxidromes
Pharmaceuticals Related Neurotoxicity
Anticholinergic Toxidrome: Case
14/F: presented to ER with a 4 d h/o dry throat, hoarse voice, & urinary hesitancy Past & Meds: acne
vulgaris (isotretinoin), ADHD (m-phenidate & guanfacine), OCs (norgestimate-ethinyl estradiol) to prevent pregnancy while on
isotretinoin. Exam: warm dry skin, mydriasis with minimal reactivity to light
Addl. info: Had been prescribed glycopyrronium tosylate (GT) wipes for hyperhidrosis,
and the patient had been applying these frequently to her axilla, neck, and face
throughout the day for the past 2 wks (instead of the manufacturers recommendation of single daily application
of a single wipe)
Note: the α-2 agonist activity from the patient’s guanfacine may have suppressed any ↑HR response seen with anticholinergic toxicity
Other settings for glycopyrrolate use:

• Premedication for anesthetic procedures
• Reverse muscarinic effects associated with neuromuscular blockade
• Drooling (ALS)
Anticholinergic
toxicity
Michael T, Paul C. A new medication, a new toxidrome - A case report of anticholinergic wipe toxicity due to improper medication use. Am J Emerg Med 2021;46:797
e791-797 e792
Anticholinergic Toxidrome
• Tricyclic antidepressants
• Antihistamines: diphenhydramine, hydroxyzine, promethazine
• Antiparkinsonian meds: trihexyphenidyl & benztropine
Michael T, Paul C. A new medication, a new toxidrome - A case report of anticholinergic wipe toxicity due to improper medication use. Am J Emerg Med
• Antipsychotics
2021;46:797 e791-797 e792/ Verheijden NA, Koch BC, Brkic Z, Alsma J, Klein Nagelvoort-Schuit SC. A 45-year-old woman with an anticholinergic toxidrome. Neth
• 2016;74:133-135/
J Med Antispasmodics Gerardi DM, Murphy TK, Toufexis M, Hanks C. Serotonergic or Anticholinergic Toxidrome: Case Report of a 9-Year-Old Girl. Pediatr
Emerg Care 2015;31:846-850.
• Antisecretory: Glycopyrrolate
• Drugs of Abuse: “Purple Drank”, Datura stramomium
Anticholinergic Toxidrome
• Features:
• Sedation/ cognitive impairment incl confusion/ delirium/
hallucinations/ psychosis
• Seizures
• Mydriasis, hyperthermia, tachycardia, anhidrosis, urinary
retention
• Typical setting:
• When used in the elderly/ patients with neurodegenerative
diseases like dementia
• Drug interactions
• Treatment:
• Supportive
• Benzodiazepines
• iv physostigmine (acetylcholinesterase inhibitor) (with central and peripheral
toxicity, crosses the blood-brain barrier)
https://litfl.com/anticholinergic-toxidrome/
Pharmaceuticals Related Neurotoxicity Sara Hocker/ Eoin Flanagan
Serotonin Syndrome: Case
20/F: admitted with MSΔ &? seizure. Meds:

Fluoxetine 80 mg/d, Trazadone 150 mg/d. Exam:
37.8C, mydriasis, hypertonicity, clonus Labs:
Tox screen positive for amphetamines & K2
Serotonin syndrome Course: improved
Rx: supportive, held fluoxetine & trazadone,

given benzodiazepine & cyproheptadine*
*(5HT2A antagonist, typical dose: 12 mg po followed by 2 mg q 2 hrs,
then 8 mg q 6 hrs, max 32 mg/d)
Buckley NA, Dawson AH, Isbister GK. Serotonin syndrome. BMJ 2014;348:g1626/ Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-20.
Serotonin Syndrome
• MAO inhibitors: phenelzine, tranylcypromine, iproniazid, isocarboxazid, selegiline, furazolidone,

linezolid, moclobemide, clorgiline, methylene blue
• Psychostimulants/ Hallucinogenics: amphetamines, methamphetamine, m-phenidate, phentermine,
MDMA, cocaine, LSD, bath salts (cathinones, phenyethylamine), “foxy methoxy” (5-
methoxydiisopropyltryptamine), Syrian rue (contains harmine & harmaline – both MAOIs)
• Opioids: meperidine, fentanyl, oxycodone, methadone, pethidine, pentazocine, tramadol, propentadol,
dextromethorphan
• SSRIs: fluoxetine, fluvoxamine, paroxetine, citalopram, sertraline, escitalopram
•Malcolm
SNRIs: venlafaxine, duloxetine
B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl) 2022;239:1881-1891/ Buckley NA, Dawson AH, Isbister
• TCAs:
GK. Serotoninclomipramine, imipramine
syndrome. BMJ 2014;348:g1626/ Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-1120/ Mason PJ, Morris VA,
• Other Antidepressants: mirtazapine, trazadone, nefazadone
Balcezak TJ. Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 2000;79:201-209.
• Other anti-infectives: ritonavir

• Anxiolytics: buspirone
• Mood stabilizers: Li, valproate, lamotrigine
• Dietary supplement: L-tryptophan, St Johns wort (Hypericum perforatum), ginseng (Panax ginseng)
• Anorexic agents: Fenfluramine, sibutramine
• Antipsychotics: risperidone
• Dopaminergics: bromocriptine, amantadine, l dopa, bupropion
• Antiemetics: ondansetron, granisetron, metoclopramide
• Antimigraine agents: sumatriptan, zolmitriptan
Serotonin Syndrome
• Though typically seen when the dose of a serotonergic agent is increased or when another serotonergic
agent is added, SS can be seen with a single dose or in context of withdrawal
• Antipyretics have no role in the management of hyperthermia in SS since the hyperthermia is driven by
muscular activity & not by a change in the hypothalamic set point
• The specific therapy is cyproheptadine; CPZ/ olanzapine can be used if NMS has been ruled out, which
at times can be a challenge…
Neuroleptic Malignant Syndrome: Case
60/M: h/o bipolar disorder & depression, admitted with MS changes (agitation) & respiratory failure. Exam:
40.5C, 160/90, 110/mt, lead-pipe rigidity, hyporeflexia. Meds: bupropion, escitalopram, fentanyl, valproate,
risperidone. Labs: CPK 8450 g/L (10-120), NaCaLFT
Neuroleptic malignant syndr./ DD: serotonin syndrome Course: improved
Rx: supportive, held meds, benzo., bromocriptine (10 mg

per NG q 8 hrs), dantrolene (Na 120 mg iv followed by 100 mg per NG q 8 hrs)
*Al Danaf J, Madara J, Dietsche C. NMS: A Case Aimed at Raising Clinical Awareness. Case Rep Med. 2015;2015:769576.
Neuroleptic Malignant Syndrome
• Dopamine receptor blocking drugs

• Typical antipsychotics: phenothiazines (CPZ, prochlorperazine, perphenazine, fluphenazine, promethazine);
butyrophenones (haloperidol), diphenylbutylpiperidine (pimozide), benzamide substitutes (sulpiride)
• Atypical antipsychotics: risperidone, olanzapine, ziprasidone, aripiprazole, clozapine,
quetiapine
• Dopamine depleters: risperidone, tetrabenazine
• Antiemetics:
Duma metoclopramide,
SR, Fung VS. Drug-induced levosulpiride,
movement disorders. clebopride,
Aust Prescr 2019;42:56-6/ domperidone,
Al Danaf droperidol,
J, Madara J, Dietsche C. NMS: A Caseitopride
Aimed at Raising Clinical
Awareness. Case Rep Med. 2015;2015:769576/ Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist 2011;1:41-47.
• Mood stabilizers: Li
• Withdrawal of dopaminergic agents: l-dopa, dopamine agonists, tolcapone, amantadine
Parkinsonism Hyperpyrexia Syndrome

(NMS-like syndrome/ acute akinesia)
Neuroleptic Malignant Syndrome
• Risk factors:
• DRBAs: multiple/ rapid escalation/ with other DA-depleting agents, depot/ parenteral
• young, men, h/o NMS, agitation, dehydration, catatonia
• Clinically: (fever, autonomic instability, MS changes)…. rigidity, hyporeflexia, ↑↑CPK…movement disorders
• Specific Rx:
• d/c DRBAs
• d/c TBZ (a DA depleter, acute/ subacute DRBA-induced MDs also worsen with TBZ d/c)
• benzodiazepines
• bromocriptine (2.5 to 5.0 mg mg tid X wks), amantadine, apomorphine
• dantrolene Na (1 to 2.5 mg/kg iv q 6 hrs)
• ECT
• DD:
• Serotonin syndrome
• Parkinsonism hyperpyrexia syndrome/ Acute akinesia
• Dyskinesia hyperpyrexia syndrome
• Anticholinergic toxidrome
• Malignant hyperthermia
.
Parkinsonism Hyperpyrexia Syndrome/ Acute Akinesia
• Setting:
• Decrease or discontinuation of antipark. Rx (e.g. failed trial)
• ↓ DA drug dose post DBS or loss of DBS stimulation as with battery failure
• Noncompliance
• Abrupt medication changes
• Withholding meds before surgery
• Enteral feeding
• Trauma, Infection, metabolic abnormalities, dehydration, concurrent illness
• Risk factors:
• Advanced PD
• Higher daily l-dopa dose
• Fluctuations/ psychosis
• Rx: admin. of antiparkinsonian Rx (NG or 50-100 mg iv l-dopa in divided doses)/ apomorphine SC injection or infusion…
Serotonin Syndrome vs Neuroleptic Malignant Syndrome/ Parkinsonism Hyperpyrexia Syndrome
Mental Time Pupils Tone Reflexes CPK BS

status
change
SS Agitated < 12 hrs Dilated ↑ (sp. ↑ ↑ ↑↑
LL)
NMS Stupor/ 1-3 days N Rigidity ↓ ↑↑↑ N/ ↓
PHS alert/ (all ms.
mute groups)
This distinction is particularly important with the parkinsonism hyperpyrexia syndrome (which
resembles NMS) & its Rx is dopaminergic therapy, which can worsen a serotonin syndrome
Seizures: Case – Cefepime Neurotoxicity
74/F: Chr. renal failure, on HD; developed bacteremia (Pantoea agglomerans sensitive to cefepime). 4 days after starting
cefepime became encephalopathic with a non focal exam. Exam: multifocal myoclonus. Inv.: CT/ LP -ve
Cefepime toxicity (later ↑↑levels confirmed) Course: Cefepime d/c, dialysis initiated, baseline in 48 hrs.
• Cefepime: 4th generation cephalosporin, broad Gm –ve , bid, excellent safety profile. (carbapenems like imipenem
also associated with seizures)
• Neuro AEs: encephalopathy, sz. Incl. nonconvulsive status, hyperexcitability/ tremors/ myoclonus
• Risk factor: renal failure (Note: neurotoxicity despite appropriate dosing)
*Fishbain JT et al. Cerebral manifestations of cefepime toxicity in a dialysis patient. Neurology. 2000;55(11):1756-71 (Index)./ Fugate JE et al. Cefepime neurotoxicity
in the ICU: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264./ Payne LE et al. Cefepime-induced neurotoxicity: a systematic review.
Crit Care. 2017;21(1):276.
Seizures: Medications
• Analgesics: opioids (meperidine, tramadol – incl. withdrawal)
• Anticancer: busulfan, chlorambucil, cytarabine, doxorubicin, etoposide, fluorouracil, IF, ifosfamide, Mtx,
mitoxantrone, nelarabine, platinum-based drugs (cisplatin), vinblastine, vincristine
• Antimicrobials: carbapenems (imipenem), cephalosporins (4th generation like cefepime), fluoroquinolones (ciprofloxacin),
INH, penicillins, metronidazole, antimalarials, antiretrovirals (C-C chemokine receptor 5 antagonist: maraviroc)
•CS, Immunosuppressants/
UpToDate/Bhattacharyya S, Darby RR, Raibagkar P, Gonzalez Castro LN, Berkowitz AL. Antibiotic-associated encephalopathy. Neurology 2016;86:963-971/ Chui
Monoclonals: aza., cyclosporine, mycophenolate, tacrolimus, muromonab (OKT3)
Chan EW, Wong AY, Root A, Douglas IJ, Wong IC. Association between oral fluoroquinolones and seizures: A self-controlled case series study. Neurology
• PsychiatricChen
2016;86:1708-1715/ meds.: antipsychotics
HY, Albertson sp. clozapine,
TE, Olson KR. Treatment atomoxetine,
of drug-induced bupropion,
seizures. Br J Clin Li, MAOI, Sutter
Pharmacol 2016;81:412-419/ SSRIs, SNRIs,
R, Ruegg serotonin
S, Tschudin-
Sutter S. Seizures as adverse events of antibiotic drugs: A systematic review. Neurology 2015;85:1332-1341/ Kim A, Kim JE, Paek YM, et al. Cefepime- Induced
modulators, TCAs (amoxapine, clomipramine, maprotiline)
Non-Convulsive Status Epilepticus (NCSE). J Epilepsy Res 2013;3:39-41/ Saboory E, Derchansky M, Ismaili M, et al. Mechanisms of morphine enhancement of
• Pulmonary
spontaneous seizure drugs: aminophylline,
activity. Anesth theophylline
Analg 2007;105:1729-1735/ Ramsay RE, Rowan AJ, Pryor FM. Special considerations in treating the elderly patient with
•3:iii2-8/
epilepsy. Neurology 2004;62:S24-29/ Grosset KA, Grosset DG. Prescribed drugs and neurological complications. J Neurol Neurosurg Psychiatry 2004;75 Suppl
Stimulants: amphetamines, cocaine, methylphenidate
Schachter SC. Iatrogenic seizures. Neurol Clin 1998;16:157-170/ Garcia PA, Alldredge BK. Drug-induced seizures. Neurol Clin 1994;12:85-99/ Messing
• Sympathomimetics
RO, & decongestants:
Closson RG, Simon RP. Drug-induced seizures: a 10-yearanorexiants (diethylpropion,
experience. Neurology phentermine, nonprescription diet aids), phenylephrine,
1984;34:1582-1586
pseudoephedrine, diphenhydramine
• Muscle relaxants/ antispasmodics: cyclobenzaprine (with OD), baclofen
• Drugs of abuse: K2/ spice, PCP, alcohol
• Parasympathetic agonists: pilocarpine
• Others: allopurinol, digoxin, DA agents, lidocaine, thyroxine, AChEI, isotretinoin, OC, ondansetron, herbal/
traditional remedies, red flower oil, herbicides, insecticides, DDAVP, hypoglycemics
• Leaders: tramadol, bupropion
• Mechanism: Lower seizure threshold or cause seizures in an OD context (like opioids)/ when used in
supratherapeutic doses (like SSRIs & SNRIs)
• Focal vs generalized: Focal-onset less likely to be drug-induced than generalized
Seizures/ Encephalopathy/ Leukoencephalopathy/ Posterior Reversible Encephalopathy Syndrome
Seizures Encephalopathy
Post. Reversible
Leukoencephalopathy
(PRES)
Leukoencephalopathy
Ifosfamide Neurotoxicity: Case
24F*: Ewing sarcoma, on etoposide & ifosfamide, presented with acute

confusion. Inv.: Brain MRI: N. EEG: triphasic waves
Ifosfamide encephalopathy (IE) Rx: d/c ifosfamide, iv methylene blue
• Ifosfamide: alkylating agent, isomer of cyclophosphamide, prodrug, activated to ifosfamide mustard

which alkylates DNA
• Ifosfamide encephalopathy:
• Clinical: 10-40%, > with oral, broad range (confusion, psychosis, seizures, EP, sensory PN etc), potentially fatal
• Inv.: MRI often N, abnormal EEG in 65% of patients receiving ifosfamide
• Mechanism: mitochondrial toxicity of ifosfamide metabolites (chloroacetaldehyde & S-carboxymethylcysteine)
• Other toxicity: hematologic, renal (reduced by mesna: Na-2-mercaptoethane sulphonate)
• Rx:
• ?methylene blue* (shortens duration, ?prevention, methylene blue is electron accepting & substitutes for flavoprotein deficiency, oxidation of
excess NADP formed in ifosfamide metabolism, inhibits amine oxidase and prevents formation of toxic metabolites, urinary excretion of glutaric acid &
sarcosine in IE)
• ?thiamine
*: also used in cyanide poisoning & MethHbemia & glutaric aciduria II
*Feyissa AM et al. Ifosfamide encephalopathy: need for a timely EEG evaluation. J Neurol Sci. 2014;336(1-2):109-12/ Ajithkumar T et al. Ifosfamide encephalopathy.
Clin Oncol. 2007;19(2):108-14/Kupfer A et al. Methylene blue & the neurotoxic mechanisms of ifosfamide encephalopathy. Eur J Clin Pharmacol 1996;50:249-252.
Pharmaceuticals Related Neurotoxicity Eoin Flanagan
Methotrexate Neurotoxicity: Case

32/F: Osteogenic sarcoma. High dose IT Mtx + leucovorin rescue. 4 days later developed encephalopathy….
Mtx induced leukoencephalopathy
• Timing: 2-14 d after Mtx

• Site: Predilection for centrum semiovale, spares subcortical U fibers
• Course: Often transient
• Rx: aminophylline (competitive inhibition of adenosine) and dextromethorphan
(NMDA antagonist, non-comp.) in addition to standard leucovorin rescue
Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic
leukemia. J Clin Oncol. 2014;32(9):949-59/ Ganesan P, Bajpai P, Shah A, Saikrishnan P, Sagar TG. Methotrexate Induced Acute Encephalopathy-Occurrence on Re-
challenge and Response to Aminophylline. Indian J Hematol Blood Transfus 2014;30:105-107/ Drachtman RA, Cole PD, Golden CB, et al. Dextromethorphan is
effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol 2002;19:319-327.
Chemotherapy – Related leukoencephalopathy: Cases
18/M: ALL, on IT-Mtx, presented 6 mths into Rx with 35/F: Colon cancer, presented with MS changes 4
sz.. MRI: (initially N) at 6 mths shown. Rx: Clinical days after 5FU. MRI: below. Rx: changed to
improvement on stopping Mtx but no f/u MRI oxaliplatin and clinical and MRI recovery in 15 days
DWI ADC
DWI ADC
b/l centrum semiovale, corona radiata, peri-ventricular deep white with sparing b/l F-P-O T2/FLAIR hyperintensity 9also IC, CC, SCP, MCP) with restricted
of subcortical U, CE –ve, no restricted diffusion diffusion, CE -ve
• May reverse/ be transient

• May have CE
• May have restricted diffusion
• This is not “chemo brain”
Sindhwani G, Arora M, Thakker VD, Jain A. MRI in Chemotherapy induced Leukoencephalopathy: Report of Two Cases and Radiologist's Perspective. J Clin Diagn
Res 2017;11:TD08-TD09.
Tacrolimus Neurotoxicity: Case
*68/M: s/p liver transplantation for PSC 10 yrs ago. On tacrolimus & mycophenolate mofetil. Presented with
cognitive decline & gait impairment.
Min. CE+
Labs: tacrolimus levels therapeutic,
CSF: N (incl PCR for JCV)
Rx & Course: tacrolimus
replaced by everolimus,
improved (clinical & imaging)
Brain biopsy: inflammatory
FLAIR
demyelination FLAIR
• Tacrolimus leukoencephalopathy: acute (PRES-like), delayed

• Other neuro AEs: tremors, PML
• Mech. of tacrolimus neurotoxicity: ?BBB disruption/ T-cell dysregulation
• Calcineurin - (tacrolimus & cyclosporine) : block T cell activation & IL-2 production
• Addl. DD of post-transplant neurologic disease: CNS infections like PML/HHV6, CNS lymphoma/ Post-
transplant lymphoproliferative disorder, CNS autoimmunity (ICP – cause AI En., AMPA/ NMDA with post-transplantation AI En. )
*Barragan-Martinez D et al. Delayed tacrolimus leukoencephalopathy. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e319/ Zhao CZ et al. Clinical reasoning:
agitation and psychosis in a patient after renal transplantation. Neurology. 2012;79(5):e41-4/ / Schuuring J et al. Severe tacrolimus leukoencephalopathy after liver
transplantation. AJNR 2003;24(10):2085-8Z
Metformin Encephalopathy: Case*
63/F*: DM2, on HD, presented with subacute onset slurred speech and walking difficulty one week after
taking metformin. Exam: Extra-pyramidal
Metformin induced
encephalopathy
• Metformin + metabolic acidosis
+ ESRD (?but also without acidosis)
• Uremic encephalopathy
• Dialysis disequilibrium
BG hypodensities T2/FLAIR hyperintensity (“lentiform fork” sign)
Narra RK. Lentiform fork sign in uraemic encephalopathy. BMJ Case Rep 2021;14/ Simon SP, Thomas J. Metformin-associated encephalopathy in HD. Indian J of
Nephrology 2019;29(3):194-196/ *Fernandes GC et al. the lentiform fork sign: an MRI pattern of metformin-associated encephalopathy. Neurology 2015;84:e15.
Middle Cerebellar Peduncle Sign: Differential Diagnosis
Posterior Reversible Encephalopathy Syndrome
s/p BMT, on tacrolimus EGPA, on mepolizumab (IL5-, NUCALA)

Anderson RC, Patel V, Sheikh-Bahaei N, et al. PRES: Puram VV, Ghazaleh D, Salari A, et al. Mepolizumab-Induced
Pathophysiology and Neuro-Imaging. Front Neurol 2020;11:463. PRES, a new patient report. BMC Neurol 2022;22:318.
Hemorrhage Hemorrhage (sulcal) Brainstem Basal ganglia/ CE (parenchymal or
(intraparenchymal) thalamus LM – dotted arrows)
PRES
UpToDate/ Shankar J, Banfield J. PRES: A Review. Can Assoc Radiol J 2017;68:147-153/I Karia SJ, Rykken JB, McKinney ZJ, Zhang L, McKinney AM. Utility and
Significance of Gadolinium-Based Contrast Enhancement in PRES. AJNR Am J Neuroradiol 2016;37:415-422/ Fugate JE, Rabinstein AA. PRES: clinical and
radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914-25
NOT
Hemorrhage Hemorrhage (sulcal) Brainstem Basal ganglia/ CE (parenchymal or
(intraparenchymal) thalamus LM – dotted arrows)
PRES
UpToDate/ Shankar J, Banfield J. PRES: A Review. Can Assoc Radiol J 2017;68:147-153/I Karia SJ, Rykken JB, McKinney ZJ, Zhang L, McKinney AM. Utility and
Significance of Gadolinium-Based Contrast Enhancement in PRES. AJNR Am J Neuroradiol 2016;37:415-422/ Fugate JE, Rabinstein AA. PRES: clinical and
radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914-25
Brain MRI showing CT showing R frontal CT showing L frontal ICH CTA “sausage on
PRES like finding (DWI/ SAH string” (of both ACAs)
SWI were N)
RCVS N
Reversible Cerebral Vasoconstriction Syndrome
• Illicit drugs: cannabis, cocaine, MDMA, amphetamines, LSD, marijuana

• Antidepressants: SSRIs, SNRIs
• -sympathomimetics/ adrenergics: NE, E, nasal decongestants (phenylpropanolamine,
pseudoephedrine, ephedrine), bromocriptine, lisuride, ephedra (ma huang)
• Antimigraine agents: Triptans, isometheptene, ergotamine derivatives
• Ergot
UpToDate derivatives:
(all images methergine,
shown here are from UpToDate)/bromocriptine, lisuride,
de Boysson H et al. PACNS cabergoline,
& RCVS: methylergonovine
A comparative study. Neurology 2018;91:e1468-e1478/ Spera K et
• Chemotherapeutics: Tacrolimus, cyclophosphamide
al. Clinical reasoning case. Neurology 2018;90:e1270-e1270/ Singhal AB et al. RCVS & PACNS. Ann Neurol 2016;79:882-894/ Ducros A. RCVS. Lancet Neurol
11:906-917, 2012/ Birnbaum J, Hellmann DB. PACNS Arch Neurol 2009; 66:704-709
• “OTCs”: Nicotine patches, binge drinking, Ginseng and other herbals, licorice, Diet pills and
energy enhancing drugs (amphetamine & related compounds, Hydroxycut)
• Immunosuppressants or blood products: IVIG,  IF, RBC transfusion, erythropoietin
• Others: phenytoin (intoxication), oral contraceptives
• Other causes: post-partum, catecholamine secreting tumors, hypercalcemia, head injury/
neurosurgery, CEA, SDH, CVT, CSF hypotension, autonomic dysreflexia
• Leaders: illicit drugs, sympathomimetics

• PRES & RCVS: Immunosuppressants (cyclosporin, tacrolimus), Cytotoxic drugs (cyclophosphamide,
Others: (IVIG, linezolid, stem cells, contrast, steroids, LSD, scorpion poison, star fruit, dimethyl
sulfoxide)
Reversible Cerebral Vasoconstriction Syndrome: Case
46/F: Presented with a thunderclap HA. Meds.: sertraline, trazodone, recently cough remedy
(dextromethorphan, guaifenesin). Exam: Balint syndrome (optic ataxia, oculomotor apraxia, simultagnosia)
Parieto-occipital infarcts Multifocal stenosis
CT head, CSF: N Rx: D/C sertraline & cold remedy RCVS
Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012;11:906-917.

Stroke
• Sympathomimetics: alpha and beta agonists (cerebrovascular vasoconstriction, arterial-rupture)

• Antiretroviral therapy: protease inhibitors
Coon EA et al. Nilotinib Rx-associated CVD & stroke . Am J Hematol. 2013;88(6):534-5/ Tefferi A. Nilotinib Rx-associated accelerated atherosclerosis…
Leukemia. •2013;27(9):1939-40/
Illicit drugs: amphetamines
Kim TD et al. Peripheral artery occlusive disease in chronic phaseCML patients treated with nilotinib or imatinib. Leukemia.
•
2013;27(6):1316-21/
Drugs Ducros A. Reversible
that cause cerebral vasoconstriction syndrome. Lancet Neurol 2012;11:906-917/ Yeung M, Bhalla A, Birns J. Recreational drug
vasculitis
misuse and stroke. Curr Drug Abuse Rev 2011;4:286-291/ Baker M, Mahad D. Drug-induced disorders of the nervous system. Clinical Medicine 2007;7:170-176.
• TNF α inhibitors
• Oral contraceptives/ Androgens
• Antihypertensives
Pharmaceuticals Related Neurotoxicity Liz Coon
Stroke: Case - TNF-

70/F: (no vascular RFs), CML developed a R MCA stroke on nilotinib
R MCA M1 stenosis (arrow), ACA stenosis Vertebrobasilar: Near occlusion of P1 of L MCA

(asterixis) both PCAs
CVD due to nilotinib
1 yr prior: note progression (MRA done for episodic confusion)

Nilotinib can cause rapidly
progressive vascular disease,
well-recognized with ponatinib;
not so with imatinib
*Coon EA et al. Nilotinib Rx-associated CVD & stroke . Am J Hematol. 2013;88(6):534-5/ Tefferi A. Nilotinib Rx-associated accelerated atherosclerosis… Leukemia.
2013;27(9):1939-40/ Kim TD et al. Peripheral artery occlusive disease in chronic phaseCML patients treated with nilotinib or imatinib. Leukemia. 2013;27(6):1316-21.
Ataxia (Cerebellar)
• Anti-infectives: metronidazole, aminoglycosides, piperazine, clarithromycin, trimethoprim, norfloxacin
• Anti-epileptics: PHT, PB, talampanel, OxCBZ, LTG, zonisamide, lacosamide, retigabine, gabapentin,
valproate
• Benzodiazepines/ Sedatives:
• Anti-neoplastics: tacrolimus, cyclosporin, cytarabine, cisplatin, oxaliplatin, carboplatin, Mtx,
doxorubicin, 5FU, vincristine
Bhattacharyya S et al. Antibiotic-associated encephalopathy. Neurology. 2016;86(10):963-71/ Agarwal A et al. Metronidazole-Induced Cerebellar Toxicity. Neurol Int.
• Li
2016;8(1):6365 (RN, VII)/ van Gaalen J, Kerstens FG, Maas RP, Harmark L, van de Warrenburg BP. Drug-induced cerebellar ataxia: a systematic review. CNS Drugs
2014;28:1139-1153/ Deik A, Saunders-Pullman R, Luciano MS. Substance of abuse and movement disorders: complex interactions and comorbidities. Curr Drug
• Anti-depressants: mirtazapine, SSRIs (fluvoxamine, paroxetine), venlafaxine
Abuse Rev 2012;5:243-253/ Woodruff BK et al Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med. 2002;346(1):68-9/
• Dissociatives: ketamine, methoxetamine
• Anti-arrhythmics: amiodarone, propafenone
• Alcohol: acute intoxication and chronic alcoholism
• Drugs of abuse: PCP, cocaine, heroin, amphetamine, methadone, dextromethorphan, solvents, toluene
• Toxins/ Metals: pesticides, Hg, Pb, Th, eucalyptus oil poisoning, CO
• Drug induced ataxia is reversible after discontinuing the drug or lowering the dosage, but specially with
phenytoin, cytarabine, Li, it may persist.
• DI ataxia can occur soon after introduction of the medication or years later (phenytoin, Val, Li) (prompting
consideration of other causes of subacute & chronic ataxia, particularly if symptoms persist or progress despite drug discontinuation)
• Li levels may be normal in Li neurotoxicity
• Patients with ataxia are particularly vulnerable to deterioration in symptoms with use of drugs that can
cause ataxia (alcohol…)
Ataxia (Cerebellar): Case - Metronidazole
62/M*: Epidural abscesses. 1 mth after metronidazole (500 mg qid) & cefepime (2 g iv bid) developed ataxia
 FLAIR dentate T2 After discontinuation of Rx
hyperintensity
Course: Metronidazole d/c ed

resolution of ataxia in 5 weeks &…
Metronidazole Toxicity
• Timing: wks after Rx initiation

• Neuro AEs: Ataxia, PN, seizures
• Imaging:
• Dentate
• RN, VII
• Restricted diffusion splenium
• Mechanism: ?free radical/ ?B1 metabolism
Bhattacharyya S et al. AB-associated encephalopathy. Neurology. 2016;86(10):963-71/ Agarwal A et al. Metronidazole-Induced Cerebellar Toxicity. Neurol Int.
2016;8(1):6365 (RN, VII)/ *Woodruff BK et al Reversible metronidazole-induced lesions of the cerebellar dentate nuclei. N Engl J Med. 2002;346(1):68-9
Aseptic Meningitis: Case
48/M: HIV X 20 yrs, was restarted on anti-retroviral Rx (etravirine, raltegravir, ritonavir, darunavir) along with TMP-SMX &
azithromycin 4 weeks ago, after having been off these meds for a year. HIV-1 viral load: 80,000 copies/ ml,
CD4 count 58/ul. Prsented with HA & photophobia. Exam: febrile with signs of meningeal irritation.
Rx: iv acyclovir, ceftriaxone, vancomycin
CSF: WBC 11, L49%; P79, G60; MRI: N

extensive microbiologic w/u -ve
Course: Day 4, TMX-SMX discontinued, complete resultion of symptoms at 1 week follow up
? Aseptic meningitis (drug-induced): DIAM
Jha P et al. A Rare Complication of Trimethoprim-Sulfamethoxazole: Drug Induced Aseptic Meningitis. Case Rep Infect Dis 2016;2016:3879406.
Aseptic Meningitis
• NSAIDs: ibuprofen, naproxen, diclofenac, sulindac
• Polyvalent IVIG
• Vaccines: MMR, hep B, diphtheria toxin 30%
• Antimicrobials: trimethoprime – sulfamethoxazole, TMP, amoxicillin, 14%
cephalosporin, valacyclovir, rifampicin, ornidazole, metronidazole
•Bihan
Monoclonal antibodies:
K, Weiss N, Theophile muromonab
H, Funck-Brentano (OKT3),B.cetuximab
C, Lebrun-Vignes Drug-induced aseptic
11%
antagonist),329 cases from the French pharmacovigilance database
(EGFR meningitis:
TNFBrαJ –Clin
analysis. Pharmacol
(infliximab, 2019;85:2540-2546
adalimumab, / Yelehe-Okouma
golimumab, cetrolizumab)M,, efalizumab
Czmil-Garon J, Pape , N, Gillet P. Drug-induced aseptic meningitis: a mini-review.8%
E, Petitpain
(anti-CD11a)
Fundam Clin Pharmacol 2018;32:252-260/Jha P, Stromich J, Cohen M, Wainaina JN. A Rare Complication of Trimethoprim-Sulfamethoxazole: Drug Induced Aseptic
ICPI (anti-CTLA4:
Meningitis. ipilimumab,
Case Rep Infect anti PD-1: nivolumab,
Dis 2016;2016:3879406/ pembrolizumab)
Cavazzana I, Taraborelli M, Fredi M, Tincani A, Franceschini F. Aseptic meningitis occurring during anti-TNF-
• AEDS:
alpha CBZ,
therapy in lamotrigine
rheumatoid arthritis and ankylosing spondylitis. Clin Exp Rheumatol 2014;32:732-734.
• Others: allopurinol, azathioprine, cytarabine, salazopyrine,

sulfasalazine, in Mtx
Note: chemical meningitis (drug-induced) - IT contrast/ CS/ aminoglycosides/ morphine,
IFN, baclofen
• Leaders: NSAIDs, IVIG, TMP-SMX, monoclonal Abs

• Mechanism: direct toxicity (specially IT) OR hypersensitivity (specially with AID)
• Clinical: …may have confusion, arthralgias, myalgias, abdominal pain, ?rash
• CSF: 100s to few 1000s cells (mean 300/ul), N CSF lactate & procalcitonin favor aseptic over bacterial
• Rule out infection/ malignancy
• Chronology: rapid onset after initiation, rapid regression after d/c, recurrence after rechallenge
Headaches
Medication Overuse Headaches

“The concept of MOH should be
viewed with more skepticism”
• Antihypertensives: nitrates, CCBs (nifedipine etc), beta-blockers, ACE-, ARBs, direct vasodilators
• Sympathomimetics (alpha and beta agonists)
• Phosphodiesterase inhibitors:
• IVIG
• OCPs
Vo ML. Commonly Used Drugs for Medical Illness and the Nervous System. Continuum (Minneap Minn) 2020;26:716-731/ Scher AI, Rizzoli PB, Loder EW.
• Anti-depressants
Medication overuse headache: An entrenched idea in need of scrutiny. Neurology 2017;89:1296-1304/ Baker M, Mahad D. Drug-induced disorders of the
• Anti-histaminics
nervous system. Clinical Medicine 2007;7:170-176.
• Antiretrovirals: efavirenz (non-nucleoside reverse transcriptase inhibitor), integrase strand transfer

inhibitors
• ?antidiuretics
• ?steroids
Cranial Nerve Dysfunction: Optic - Pseudotumor Cerebri
Lee A, Wall M. UpToDate. Accessed Dec 2023

Cranial Nerve Dysfunction: 3, 4, 6
DRUG REPORTED EFFECTS

Diazepam ↓saccadic peak velocity, impairs smooth pursuit & gaze-holding,
↓VOR amp
TCAs, Opiates INO, total gaze paresis
Phenytoin Impaired smooth pursuit & gaze-holding, downbeat nystagmus,
periodic alternating nystagmus, total gaze paresis
Phenobarb & Impaired smooth pursuit & gaze holding, impaired vergence, total
others gaze paresis, ↓accommodative convergence/ accommodation ratio
CBZ Ophthalmoplegia, oculogyric crisis, downbeat nystagmus
Phenothiazines Oculogyric crisis, INO
Methadone Saccadic hypometria, impaired smooth pursuit
Alcohol & Impaired smooth pursuit & gaze holding (ETOH may cause
marijuana positionally induced nystagmus)
Chloralhydrate Impaired smooth pursuit
Amphetamines Increased accommodative convergence/ accommodation ratio
Chlodecone Opsoclonus
(organochlorine
insecticide),
lithium, thallium
Leigh & Zee: The Neurology of Eye Movements/ Rizzo M, Corbett J. B/L INO reversed by
naloxone. Arch Neurol 1983;40:242-243.
Myelopathy
• Chemotherapy: methotrexate (sp. IT), nelarabine

Amer-Salas N, Gonzalez-Morcillo G, Rodriguez-Camacho JM, Cladera-Serra A. Nelarabine-associated myelopathy in a patient with acute lymphoblastic
leukaemia: Case report. J Oncol Pharm Pract 2021;27:244-249/ Picca A, Berzero G, Bihan K, et al. Longitudinally Extensive Myelitis Associated With Immune
• Radiation:
Checkpoint Inhibitors. Neurol Myelitis, early
Neuroimmunol Neuroinflamm 2021;8/delayed, late delayed
Kunchok A, Aksamit AJ, Jr., Davis JM, 3rd, et al. Association Between Tumor Necrosis
• TNF α –
Factor Inhibitor Exposure and Inflammatory Central Nervous System Events. JAMA Neurol 2020;77:937-946/ Kunchok A, Zekeridou A, Pittock S. CRMP5-IgG-
Associated Paraneoplastic Myelopathy With PD-L1 Inhibitor Therapy. JAMA Neurol 2020;77:255-256/ Sharma R, Sorenson EJ. Enhancing cord lesions with
• Clin
nitrous-oxide toxicity. Arch ICPCase-: Rep.
at times with
2019;2(1)/ KhanCRMP
M, Ambady5/P,ANNA1/
Kimbrough GFAP/ AQP4
D, et al. Radiation-Induced Myelitis: Initial and Follow-Up MRI and
• Drugs of abuse: heroin, nitrous oxide, cocaine
Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years. AJNR Am J Neuroradiol 2018;39:1576-1581/ Bradshaw MJ, Mobley BC,
Zwerner JP, Sriram S. Autopsy-proven demyelination associated with infliximab treatment. Neurol Neuroimmunol Neuroinflamm 2016;3:e205/ Psimaras D,
• D,Toxins:
Tafani C, Ducray F, Leclercq Feuvret L, organophosphates,
Delattre JY, et al: Bevacizumabsolvents
in late-onset radiation-induced myelopathy. Neurology 2016;86:454-457/ Kissoon
• Zinc
NP, Graff-Radford J, Watson JC, Laughlin R. SC injury from fluoroscopically guided intercostal blocks with phenol. Pain Physician 2014; 17(2):E219-24/
Chamberlain MC, Eaton KD, Fink J: Radiation-induced myelopathy: treatment with bevacizumab. Arch Neurol 68:1608-1609, 2011/ Nyffeler T, Stabba A,
Sturzenegger M. Progressive• myelopathy
Others: phenol
with selective involvement of the lateral and posterior columns after inhalation of heroin vapour. J Neurol
2003;250:496-498/ McCreary M, Emerman C, Hanna J, Simon J. Acute myelopathy following intranasal insufflation of heroin: a case report. Neurology
2000;55:316-317.
Pharmaceuticals Related Neurotoxicity Eoin Flanagan
Myelopathy: Case - Methotrexate

26/M: DLBCL with CNS involvement, s/p recent Rx with IT Mtx. Presents with subacute onset progressive
paraplegia.
T1+C T2 T2
Mtx induced myelopathy
Rx: d/c Mtx, folate
T2 Labs: MTHFR polymorphism

(A1298C homozygosity)
• M of A: antimetabolite (interferes with DNA synthesis/ repair, and cellular replication, inhibits DHFR; Mtx damages endothelial spinal capillaries)
• Other neuro AEs: stroke-like episodes, leukoencephalopathy, aseptic meningitis (IT only)
• Risk: C677T & A1298C polymorphisms associated with increased risk of myelopathy (also hematologic, hepatic,
mucosal toxicity). (The polymorphisms cause  enzyme activity; Consider testing for MTHFR mutation prior to use, avoid in homozygotes)
• Rx: ?SAM, methionine, leuvovorin, B12
Tariq H et al. IT-Mtx Necrotizing Myelopathy: A Case Report and Review of Histologic Features. Clin Med Insights Pathol 2018;11:1179555718809071/ Juster-Switlyk K
et al. MTHFR C677T polymorphism is associated with methotrexate-induced myelopathy risk. Neurology. 2017;88(6):603-4.
Myelopathy: Cases - Nitrous oxide, Phenol (intercostal block)
52/F: myelopathy within mts of a R T7-9 intercostal
21/M: “whippets” 200 hits/day
nerve block with phenol
Sharma R, Sorenson EJ. Enhancing cord lesions Kissoon NP, Graff-Radford J, Watson JC, Laughlin R. SC injury from
with N2O toxicity. Arch Clin Case Rep. 2019;2(1) fluoroscopically guided IC blocks with phenol. Pain Physician 2014; 17(2):E219-24.
Myelopathy: Cases – Heroin (TM-like or Tractopathy)
McCreary M, Emerman C, Hanna J, Simon J. Acute myelopathy following Nyffeler T, Stabba A, Sturzenegger M. Progressive myelopathy with selective
intranasal insufflation of heroin: a case report. Neurology 2000;55:316-317. involvement of the lateral and posterior columns after inhalation of heroin
vapour. J Neurol 2003;250:496-498.
Myelopathy: Radiation
54/M: H/O Sq. cell ca. (Rx with surgery & XRT: 4800 cGy). 15 mths later developed paraparesis with T3 level.
T1+C: enhancing nodular T2: C5-T8 cord edema
lesion at C7-T1
Rx with 4 cycles of bevacizumab: 5

• Types:
mg/kg once every 2 weeks

Acute
Early delayed
Late delayed
• Bevacizumab:
Imaging
improvement >
?clinical
…and clinical improvement
Chamberlain MC, Eaton KD, Fink J: Radiation-induced myelopathy: treatment with bevacizumab. Arch Neurol 68:1608-1609, 2011/ *Psimaras D, Tafani C, Ducray F,
Leclercq D, Feuvret L, Delattre JY, et al: Bevacizumab in late-onset radiation-induced myelopathy. Neurology 2016;86:454-457
Peripheral Neuropathy
Staff NP. PN due to vitamin and mineral deficiencies, toxins, and medications. Continuum 2020;26:1280-1298/ Santomasso BD. Anticancer Drugs and the
Nervous System. Continuum 2020;26:732-764/ Vo ML. Commonly used drugs for medical illness and the nervous system. Continuum 2020;26:716-731/ Jones MR
•et al.
Chemotherapeutic
Drug-Induced PN: A Narrative agents:
Review. Curr Clin Pharmacol 2020;15:38-48/ Staff NP et al. Chemotherapy-induced PN. Ann Neurol. 2017;81(6):772-81/
Morales D et al. Association between PN and exposure to oral fluoroquinolone or amoxicillin-clavulanate therapy. JAMA Neurol 2019;76:827-833/Islam B et al.
Vinca•alkaloids,
Traditional
thalidomidechemotherapy:
and eribulin-induced platinum-based
peripheral neurotoxicity:agents (cisplatin, to
From pathogenesis oxaliplatin,
treatment. J Peripher,Nerv
carboplatin) taxanes (cabazitaxel,
Syst 2019;24 paclitaxel,Staff
Suppl 2:S63-S73/
NP et al. Platinum-induced peripheral
nab-paclitaxel, docetaxel) , vinca alkaloids
neurotoxicity: From pathogenesis to treatment.
(vincristine, vindesine, J Periphervinflunine,
vinblastine, Nerv Syst vinorelbine) , topoisomerase
2019;24 Suppl 2:S26-S39/Tamburin Sinhibitors
et al. Taxane
and epothilone-induced peripheral neurotoxicity. J Peripher Nerv Syst 2019;24 Suppl 2:S40-S51/Velasco R et al. Bortezomib and other proteosome inhibitors-
(camptothecins,
induced peripheral irinotecan,
neurotoxicity. topotecan)
J Peripher Nerv, anti-metabolites (cytarabine,
Syst 2019;24 Suppl 2:S52-S62/ gemcitabine,
Romagnolo nelarabine), epothilones
A et al. Levodopa-Induced Neuropathy: (Aixabepilone)
Systematic,Review. Mov
eribulin,
Disord Clin podophyllotoxins
Pract 2019;6:96-103/ Shah A et al. Incidence and disease
(etoposide, , fludarabine,
burden
teniposide) alkylating
of chemotherapy-induced agents
peripheral neuropathy , ado-
in a population-based
(ifosfamide) cohort.
JNNP2018;89:636-641/ Staff NP et al. Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol 2017;81:772-781/ Kumar S et al. Management
of adversetrastuzumab,
events associated suramin,
with ixazomib arsenic trioxide, 5FU, 5-azacytidine
plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. Br J Haematol 2017;178:571-582/ Baratta
JM et•al. Vasculitic
Small molecule inhibitors:
neuropathy following exposure proteosome inhibitors
to minocycline. Neurol Neuroimmunol Neuroinflamm
(bortezomib, 2016;3:e180/
carfilzomib, ixazomib) , larotrectinib,
Dalla lorlatinib
Torre C et al. Lenalidomide long-term
neurotoxicity: Clinical and neurophysiologic prospective study. Neurology 2016;87:1161-1166/ Kandula T et al. Pediatric chemotherapy induced PN. Cancer
Treat •RevAnti-VEGF:
2016;50:118-128/ sorafenib, sunitinib,
Jugel C et al. Neuropathy thalidomide,
in Parkinson's lenalidomide,
disease patients with intestinalpomalidomide
levodopa infusion versus oral drugs. PLoS One
• Biologics/
2013;8:e66639/ Arnold R etimmunomodulatory:,
al. Association between calcineurinbrentuximab vedotin
inhibitor treatment and peripheral nerve
(anti-CD30, sensory), in
dysfunction
mild TNF inhibitors
renal transplant recipients. Am J
(adalimumab,
Transplant 2013;13:2426-2432/ Grisold W et al. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention.
infliximab,
Neuro Oncol 2012;14etanercept; also CNS
Suppl 4:iv45-54/ Orr demyelination) IF (β) characteristics, and risk factors for amiodarone neurotoxicity. Arch Neurol 2009;66:865-
CF, Ahlskog JE., Frequency,
• Immunotherapy
869/ Liedorp agents:
M et al. Axonal neuropathy atezolizumab,
with prolonged avelumab,
sulphasalazine use. Clin Exp durvalumab, daratumumab,
Rheumatol 2008;26:671-672./ ipilimumab/
1.Baker M, Mahad D. Drug-induced disorders
of the nervous system. Clinical Medicine 2007;7:170-176/Chang MH, Lin KP, Wu ZA, Liao KK. Acute ataxic sensory neuronopathy resulting from podophyllin
tremelimumab
intoxication. , nivolumab/
(anti CTLA-4)Goodheart
Muscle Nerve 1992;15:513-514/ RS et al. pembrolizumab , ado-trastuzumab
(anti PD-1)neuropathy--clinical
Phenelzine associated peripheral emtansinefindings. Aust N Z
and electrophysiologic
J Med• 1991;21:339-340/Johnston
Aromatase inhibitors: anastrozole,
SR et al. Peripheral neuropathyexemestane
associated with lithium toxicity. J Neurol Neurosurg Psychiatry 1991;54:1019-102/ Pedersen PB
et al. Penicillamin-induced neuropathy in rheumatoid arthritis. Acta Neurol Scand 1990;81:188-190/ Pouget J et al. [Peripheral neuropathy during treatment with
• Anti-folate:
cimetidine]. pemetrexed
Rev Neurol (Paris) 1986;142:34-41/ (sensory)
Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med 1984;101:92-104/ Schaumburg
H et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 1983;309:445-448.
PN generally not seen with doxorubicin, alkylating agents (like nitrosoureas/ procarbazine/ cyclophosphamide),
methotrexate, certain monoclonal antibodies (like bevacizumab/ trastuzumab)
Peripheral Neuropathy: Chemotherapy
Approx. 40% of patients receiving neurotoxic chemotherapy will suffer from CIPN
Generally distal, axonal, > sensory, dose-dependent, partially reversible
Platinum-based Taxanes Vina alkaloids Proteosome inhibitors
Agents Cisplatin, lipoplatin Paclitaxel, docetaxel, Vincristine, vindesine, Bortezomib, carfilzomib,

(liposomal formulation), abraxene (albumin-bound vinblastine, vinflunine, ixazomib
carboplatin, oxaliplatin paclitaxel), nab-paclitaxel, vinorelbine
cabazitaxel
Unique features Sensory ganglionopathy Diffuse pain syndrome with Early sensory Painful sensory
(Lhermitte, sensory ataxia) myalgias/ arthralgias Motor also (ankle/ toe
Coasting (immediate: associated with dorsiflexion, wrist extension)
Cold –induced hyperalgesia later PN) Autonomic
(oxaliplatin, immediate) Motor also Vocal cord paralysis
Autonomic Dysguesia
Smell, taste, vestibular, Autonomic
hearing
Reversibility + + + +++
Mechanism Sensory ganglia, absence of Microtubules, mitochondria, Microtubules, mitochondria Proteosome inhibitor…
mitochondrial DNA repair nerve terminals
processes, Na channel
(oxaliplatin)
Peripheral Neuropathy
Staff NP. PN due to vitamin and mineral deficiencies, toxins, and medications. Continuum 2020;26:1280-1298/ Santomasso BD. Anticancer Drugs and the
•
Nervous System. Continuum 2020;26:732-764/
Immunosuppressives (Other):Vo ML. Commonly used drugs
chloroquine, gold forsalts,
medicalleflunomide,
illness and the nervous –
system. Continuum
calcineurin 2020;26:716-731/ Jones MR
(cyclosporine,
et al. Drug-Induced PN: A Narrative Review. Curr Clin Pharmacol 2020;15:38-48/ Staff NP et al. Chemotherapy-induced PN. Ann Neurol. 2017;81(6):772-81/
Morales tacrolimus)
D et al. Association between PN and exposure to oral fluoroquinolone or amoxicillin-clavulanate therapy. JAMA Neurol 2019;76:827-833/Islam B et al.
• Cardiovascular
Vinca alkaloids, thalidomide and eribulin-induced
agents: peripheral neurotoxicity:
amiodarone, procainamide, From pathogenesis
hydralazine, to treatment.
statinsJ Peripher Nerv Syst 2019;24 Suppl 2:S63-S73/ Staff
NP et al. Platinum-induced peripheral neurotoxicity: From pathogenesis to treatment. J Peripher Nerv Syst 2019;24 Suppl 2:S26-S39/Tamburin S et al. Taxane
and• epothilone-induced
Antimicrobials: INH/neurotoxicity.
peripheral hydralazine Nerv Syst, 2019;24
(B6 depletion)
J Peripher ethambutol, ethionamide,
Suppl 2:S40-S51/Velasco linezolid,
R et al. Bortezomib andmetronidazole, azoles,
other proteosome inhibitors-
induced peripheral neurotoxicity.
dapsone J Peripher
(motor/ multiple) Nerv Syst 2019;24 Suppl
, chloramphenicol, 2:S52-S62/ Romagnolo
fluroquinolones, A et al. Levodopa-Inducednitrofurantoin,
aminoglycosides, Neuropathy: A Systematic Review. Mov
penicillins,
Disord Clin Pract 2019;6:96-103/ Shah A et al. Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort.
sulfonamides,
JNNP2018;89:636-641/ colistin,
Staff NP minocycline peripheral neuropathy: A current review. Ann Neurol 2017;81:772-781/ Kumar S et al. Management
et al. Chemotherapy-induced
of •adverse events associated Nucleoside
Antiretrovirals: with ixazomib plus lenalidomide/dexamethasone
reverse transcriptase in- relapsed/refractory multiple myeloma.
(ddC, ddI, d4T, lamivudine, stavudine)Br , J Haematol
c-c 2017;178:571-582/
chemokine Baratta
receptor 5
JM et al. Vasculitic neuropathy following exposure to minocycline. Neurol Neuroimmunol Neuroinflamm 2016;3:e180/ Dalla Torre C et al. Lenalidomide long-term
antagonist
neurotoxicity: (maraviroc)
Clinical and neurophysiologic prospective study. Neurology 2016;87:1161-1166/ Kandula T et al. Pediatric chemotherapy induced PN. Cancer
•
Treat Rev 2016;50:118-128/
Vitamins: B 6
Jugel C et al. Neuropathy in Parkinson's disease patients with intestinal levodopa infusion versus oral drugs. PLoS One
2013;8:e66639/ Arnold R et al. Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J
• Drugs
Transplant of abuse: Grisold
2013;13:2426-2432/ N20 W et al. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention.
•
Neuro Oncol 2012;14
Others: Suppl 4:iv45-54/
disulfiram, Orr CF, Ahlskog
phenytoin, JE. Frequency,
l-dopa, characteristics,
colchicine, and risk factors?
sulfasalazine, forpenicillamine,
amiodarone neurotoxicity.
? Arch Neurol 2009;66:865-
phenelzine,,
869/ Liedorp M et al. Axonal neuropathy with prolonged sulphasalazine use. Clin Exp Rheumatol 2008;26:671-672./ 1.Baker M, Mahad D. Drug-induced disorders
?
of the lithium, ?statins
nervous system. Clinical Medicine 2007;7:170-176/Chang MH, Lin KP, Wu ZA, Liao KK. Acute ataxic sensory neuronopathy resulting from podophyllin
intoxication. Muscle Nerve 1992;15:513-514/ Goodheart RS et al. Phenelzine associated peripheral neuropathy--clinical and electrophysiologic findings. Aust N Z
J Med 1991;21:339-340/Johnston SR et al. Peripheral neuropathy associated with lithium toxicity. J Neurol Neurosurg Psychiatry 1991;54:1019-102/ Pedersen PB
•et al.Amiodarone – neurotoxicity,
Penicillamin-induced including
neuropathy in rheumatoid arthritis.PN, may Scand
Acta Neurol be less than what
1990;81:188-190/ wasJ etreported
Pouget earlier,
al. [Peripheral probably
neuropathy due to
during treatment with
cimetidine]. Rev Neurol (Paris) 1986;142:34-41/ Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med 1984;101:92-104/ Schaumburg
H etlower maintenance
al. Sensory neuropathy fromdoses
pyridoxinebeing
abuse. Aused (200 mg/syndrome.
new megavitamin d vs 600 mg/
N Engl d earlier)
J Med 1983;309:445-448.
• INH/ hydralazine: B6 depletion
• Intestinal l-dopa gel associated with PN, possible due to high l-dopa doses or malnutrition resulting
from intestinal drug application
Peripheral Neuropathy: Case – Minocycline (Vasculitic Neuropathy)
17/F: 3 yrs h/o acne, on minocycline. Developed a R med. medullary ischemic stroke + axonal multiple
mononeuropathies. w/u: -ve except…L sup. Radial nerve biopsy: necrotizing vasculitis
H&E: epineural nerve large arteriole necrotizing vasculitis, Methylene blue stain: myelinated fiber degeneration in Minocycline induced
infl. infiltrate, disruption of all wall layers, fibrinoid necrosis center of fascicle typical of ischemic change
autoimmune
vasculitis
Rx & Course: d/c

minocycline, iv m-
pred., improved
• AI disorders associated with minocycline: systemic/nonsystemic vasculitis, drug-induced lupus, serum

sickness, AI hepatitis
• Mechanism: hapten mediated, typically chronic exposure
*Baratta JM, Dyck PJ, Brand P, Thaisetthawatkul P, Dyck PJ, Engelstad JK, et al. Vasculitic neuropathy following exposure to minocycline. Neurol Neuroimmunol
Neuroinflamm. 2016;3(1):e180.
Neuromuscular junction dysfunction (Myasthenia Gravis)
• Anesthetic agents: neuromuscular blockers & inhalational anesthetics (isoflurane, halothane), lidocaine iv
• Antibiotics: fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin), macrolides (azithromycin, clarithromycin, erythromycin),
aminoglycosides (gentamycin, neomycin, tobramycin), ketolides (telithromycin), antiretrovirals (ritonavir), clindamycin,
metronidazole, nitrofurantoin, vancomycin, tetracyclines (doxycycline, tetracycline), polymyxins, ?penicillin
• Cardiovascular drugs: Antiarrhythmics (Class Ia: procainamide, quinidine), ?beta-blockers (atenolol, labetalol, metoprolol,
propranolol)
Bird, , ?CCBs
SJ. UpToDate. (L type)
Accessed Dec 2022 UpToDate 2022/ Sheikh S, Alvi U, Soliven B, Rezania K. Drugs That Induce or Cause Deterioration of Myasthenia
• Gravis:
Antipsychotics:
An Update. J Clin ?Butyrophenones
Med 2021;10/ / Vacchiano V,(haloperidol) , ?phenothiazines
Solli P, Bartolomei I, Lai G, Liguori R, Salvi F. Exacerbation
(CPZ, of myasthenia gravis after amoxicillin
prochlorperazine)
therapy: a case series. Neurol Sci 2020;41:2255-2257.
• AEDs: CBZ, ethosuximide, gabapentin, phenobarb, phenytoin
• Steroids: dexamethasone, m pred., prednisone
• Ophthalmic drugs: betaxolol, echothiophate, proparacaine, timolol, tropicamide
• Immunotherapy agents: atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab,
• Others: Botox, chloroquine/ hydroxy, penicillamine, quinine, Mg, cisplatinum, emetine (ipecac syrup),
fludarabine, glatiramer acetate, statins, ?IF α, IL2, iodinated contrast, riluzole, TK-, statins, Li,
antiretroviral (ritonavir)
• Induce de novo MG/ MG exacerbation by altering the immune response: ICP -, penicillamine, IF
• Cause MG-like symptoms/ unmask MG/ exacerbate MG through effects of NMJ transmission: anesthetic
agents, antibiotics (macrolides, fluoroquinolones, aminoglycosides, penicillins), cardiac drugs (1 a antiarrhythmics, CCB – L type),
antipsychotics, steroids, Botox, Mg
• Both: TK -, statins, Li
• The steroid paradox
Muscle Disease
• Direct myotoxicity: glucocorticoids, lipid-lowering drugs (cerivastatin > fluvastatin > simvastatin > atorvastatin/ pravastatin),
antimalarials (chloroquine/ hydroxychloroquine- vacuolar myopathy), colchicine (vacuolar myopathy), zidovudine (mitochondrial
myopathy)
UpToDate/ Santomasso BD. Anticancer Drugs and the Nervous System. Continuum (Minneap Minn) 2020;26:732-764 / Harmon DM et al. 76-Year-Old Woman With
•Generalized
Indirect muscle
Weakness. Mayo damage: ischemic
Clin Proc 2019;94, muscle
2546-2550/ compression
Pinal-Fernandez in drug
I, Casal-Dominguez induced
M, Mammen AL. coma, ↓K related
Immune-Mediated myopathy
Necrotizing Myopathy. Curr
with diuretics,
Rheumatol Rep 2018;20:21/muscle
Milone M: damage due
Diagnosis and to hyperkinetic
Management states/
of Immune-Mediated seizures/
Myopathies. Mayodystonia/
Clin Proc 2017;hyperthermia/
92:826-837/ Colmenares EW, Pappas AL.
Proton Pump Inhibitors: Risk for Myopathy? Ann Pharmacother 2017;51:66-71/ Harada Y, Virmani T, Gokden M, Stefans V. Toxic Myopathy due to Antidopaminergic
?DA antagonists
Medication Without Neurolepticeven without
Malignant NMS
Syndrome. J Clin Neuromuscul Dis 2018;20:94-98/ Kassardjian CD et al. Clinical Features and Treatment Outcomes of
•Necrotizing
Immunologically induced
Autoimmune Myopathy. JAMA inflammatory myopathy:
neurology 2015;72:996-1003/ PasnoorTNF -, IFRJ,,Dimachkie
M, Barohn ICP – (atezolizumab,
MM. Toxic myopathies.avelumab,
Neurol Clin 2014;32:647-670/
Luton K, Garcia C, Poletti E, Koester G. Nicolau Syndrome: three cases and review. Int J Dermatol 2006;45:1326-1328/ Grosset KA, Grosset DG. Prescribed drugs
and durvalumab, ipilimumab,
neurological complications. nivolumab,
J Neurol Neurosurg pembrolizumab),
Psychiatry 2004;75 Suppl 3:iii2-8/D-penicillamine,
Sagman DL, Melamed JC. statins
L-tryptophan-induced eosinophilia-myalgia
•syndrome
Cancer therapies
and myopathy. (traditional):
Neurology docetaxel/ paclitaxel, brentuximab, gemcitabine,
1990;40:1629-1630.
• Drugs of abuse: alcohol, cocaine, heroin
• Others: oral retinoids (isotretinoin), ?PPIs
• IM injections: of opiates can cause muscle damage with a fibrotic reaction
• Steroid myopathy: vs Inflammatory myopathy

• Statins: myalgias, myopathy, myositis, myonecrosis, rhabdomyolysis…sp. with NM disorders, medical
disease like hypothyroidism/ vit. D deficiency, renal infsufficiency, DIs (with CYP34A – like cyclosporine, macrolides, azole
antifungals, HCV/ HIV protease -, CCBs, amiodarone OR with other myotoxic drugs like fibrates, niacin, colchicine etc)
• Anti-psychotics: ?Myopathy independent of NMS
Margherita Milone Pharmaceuticals Related Neurotoxicity
Myopathy: Case – Necrotizing Autoimmune Myopathy
76/F: 1 yr h/o progressive proximal limb weakness & SOB. Exam: facial, neck flexor & proximal UL-LL &
distal LL limb weakness. Statin use 6 & 3 yrs prior. Stopped due to LL weakness. Labs: CPK: 5608 U/L (N:
38-176). EMG: severe diffuse myopathy with fibrillations & myotonic D/C.
Necrotic fibers & regenerating fibers Necrotic fibers invaded by Anti HMGCR Ab: 87 U (N <20)
(H&E) macrophages (Acid PO4ase) CT C/A/P: -ve
Necrotizing AI Myopathy
Rx: IVIG, steroids, Mtx
•Clinically: can start yrs after starting Rx/ may start after statin d/c/ can progress for mths. despite drug
discontinuation; myopathy with dyspnea & dysphagia, facial & neck weakness, (rare: cardiac involvement)
•Associations: CTD, cancer, HIV, idiopathic in 50% (Care: statins in dietary constituents)
•Labs/ Imaging/ EMG/ path: CPK, autoAb (SRP/ HMGCR), MRI: muscle edema, EMG: denervation potentials
& myopathic units, pseudomyotonia, Path: necrotic muscle fibers with minimal/ no inflammation
•Rx: Early & aggressive immunotherapy improves outcomes (more than steroid monotherapy, often triple
therapy, IVIG/ Rituximab & steroid sparing therapy: Mtx/ Aza/ Myco Mofetil…?abatacept/ tocilizumab
Harmon DM et al. 76-Year-Old Woman With Generalized Weakness. MCP 2019;94, 2546-2550/ Milone M: Diagnosis and Management of Immune-Mediated Myopathies.
MCP 92:826-837, 2017/ Kassardjian CD et al. Clinical features & Rx outcomes of NAIM. JAMA neurology 2015;72:996-1003/
Muscle Disease: Rhabdomyolysis
• Nonexertional, Nontraumatic
• Prescription drugs:
• Lipid-lowering: statins, fibrates
• Psychiatric
UpToDate/ Santomasso BD.meds.:
Anticancerantipsychotics,
Drugs and the NervousLi, SSRIs,
System. valproate
Continuum (Minneap Minn) 2020;26:732-764 / Harmon DM et al. 76-Year-Old
Woman With Generalized Weakness. Mayo Clin Proc 2019;94, 2546-2550/ Pinal-Fernandez I, Casal-Dominguez M, Mammen AL. Immune-Mediated
• Anti-infectives:
Necrotizing Myopathy. Curr Rheumatolprotease -, trimethoprim-sulfamethoxazole,
Rep 2018;20:21/ quinolones,Myopathies.
Milone M: Diagnosis and Management of Immune-Mediated amphotericin
Mayo Clin BProc 2017;
• Anaesthetics:
92:826-837/ Colmenares EW, Pappas Volatile (halothane,
AL. Proton isoflurane,
Pump Inhibitors: sevoflurane,
Risk for Myopathy? desflurane)
Ann Pharmacother + succinylcholine
2017;51:66-71/ Harada Y, Virmani T, Gokden M,
Stefans V. Toxic Myopathy due to Antidopaminergic Medication Without Neuroleptic Malignant Syndrome. J Clin Neuromuscul Dis 2018;20:94-98/
• Supplements:
Kassardjian strength
CD et al. Clinical Features training
and Treatment upplements,
Outcomes ephedra,
of Necrotizing Autoimmunecreatine,
Myopathy. JAMAlarge caffeine
neurology doses Pasnoor M,
2015;72:996-1003/
Barohn• RJ,Others:
DimachkieEACA,
MM. Toxic erlotinib/ sunitinib,
myopathies. Neurol colchicine,
Clin 2014;32:647-670/ steroids,
Luton K, Garcia C,vasopression, narcotics,
Poletti E, Koester G. Nicolau antihistaminics
Syndrome: three cases and
review. Int J Dermatol 2006;45:1326-1328/ Grosset KA, Grosset DG. Prescribed drugs and neurological complications. J Neurol Neurosurg Psychiatry
•2004;75
DrugsSupplof abuse:
3:iii2-8/ Sagmancocaine,
DL, Melamedamphetamines/ meth.,
JC. L-tryptophan-induced LSD, heroin,
eosinophilia-myalgia ETOHand myopathy. Neurology 1990;40:1629-1630.
syndrome
• Others: infections, toxins (CO, venom, mushroom, quail (galeopsis ladanum seed)), electrolytes, DM/ thyroid
• Non traumatic exertional: exertion +++, hypo/ hyperthermia incl. NMS/ malignant hyperthermia, muscle
disease (metabolic myopathy/ congenital myopathy/ muscular dystrophy), ↓K, sickle cell trait, hyperkinetic states (incl. seizures)
• Traumatic: crush, immobilization/ restraint, surgery, compartment syndrome, vascular compression,
electrocution/ burn injury
• Statins: Rhabdomyolysis risk ↑es with predisposing states incl. inflammatory myopathy
• Dietary supplements: weight loss/ enhanced physicial performance (ephedra/ ?creatine/ ?large amounts of caffeine)
• ETOH: coma, agitation, direct ms. toxicity, ↓K, ↓PO4
leaders
Postural + rest tremors Pharmaceuticals Related Neurotoxicity
Parkinsonism
• Dopamine receptor blocking drugs

• Typical antipsychotics: phenothiazines (CPZ, prochlorperazine, perphenazine, fluphenazine,
promethazine); butyrophenones (haloperidol), diphenylbutylpiperidine (pimozide), benzamide
substitutes (sulpiride)
• Atypical antipsychotics: risperidone, olanzapine, ziprasidone, aripiprazole, clozapine, quetiapine
• Dopamine depleters: risperidone, tetrabenazine
• Antiemetics: metoclopramide, levosulpiride, clebopride, domperidone, itopride
Zhou, DJ et al. Movement disorders associated with anti-seizure medications: A systematic review. Epilepsy behavior. 2022;131: 108693
Vo ML. • Commonly
Calcium channel
Used antagonists:
Drugs for Medical flunarizine
Illness and the > cinnarizine,
Nervous System. (diltiazem,
Continuum (Minneap verapamil) SA, Burkhard PR, Caroff S,
Minn) 2020;26:716-731/Factor
et al. •Recent
Mood stabilizers:
developments lithium
in drug-induced movement disorders:
(can cause a mixed
Parkinsonism picture.
even Lancet neurol
with therapeutic 2019;18:880-890/ Janssen S, Bloem BR, van de
levels)
Warrenburg BP. The clinical heterogeneity of drug-induced myoclonus: an illustrated review. J Neurol 2017;264:1559-1566/ Deik AF, Shanker VL. A case of
• AEDS: valproate,
amiodarone-associated myoclonus (phenytoin, levetiracetam)
responsive to levetiracetam. Can J Neurol Sci 2012;39:680-681/ Jankovic J. In Bradley’s Neurology in clinical practice
• Antidepressants: SSRIs (citalopram, fluoxetine, paroxetine, sertraline), MAO-, bupropion
• Antihistaminics
• Chemotherapeutic agents: cytosine arabinoside, cyclophosphamide, vincristine, adriamycin,
doxorubicin, paclitaxel, etoposide
• Immunosuppressive drugs: cyclosporine, tacrolimus
• Toxins: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), OP pesticides, Mn, methanol, CN, CO, CS2,
amphetamine, MDMA, opioid overdose (CHANTER syndrome)
• Others: ? amiodarone
Drug-Induced Parkinsonism vs Parkinson Disease
• DIP vs PD: Though DIP is classically a b/l symmetric, akinetic-rigid syndrome, without rest tremors (possibly
with orolingual dyskinesias); in many it may be asymmetric & with rest tremors, making the distinction difficult.
Early postural instability may be seen, but festination/ freezing is uncommon.
• Rx: d/c or ↓drug; if antipsychotics are a must: consider quetiapine or clozapine
• Course: develops in few wks-mths, in some it may resolve despite continuing DRBAs suggesting
tolerance; DIP can take mths or even years to resolve after inciting drug is stopped; or it may not…
• ?PD “waiting to happen”: Could DIP simply be unmasking subclinical PD?
• Role of dopamine replacement therapy: If parkinsonism persists (which it may in 15-45%!), could PD have
been unmasked…hence…Rx as PD option (despite the fact that mechanism is DA receptor blockade)
*Silver M, Factor SA. Valproic acid-induced parkinsonism: levodopa responsiveness with dyskinesia. Parkinsonism Relat Disord. 2013;19(8):758-60/ Shin HW,
Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21.
Tremors
• Antidepressants: SSRIs, TCAs, venlafaxine, bupropion

• Mood stabilizers: lithium
• AEDs: valproate, lamotrigine
• Sympathomimetics (alpha and beta agonists): pseudoephedrine, theophylline, bronchodilators
(albuterol, salmeterol)
Factor SA,•Burkhard
Cardiac drugs:
PR, Caroff amiodarone,
S, et al. CCBs
Recent developments in drug-induced movement disorders: a mixed picture. Lancet neurol 2019;18:880-890/ Bhatia KP,
• Immunosuppressives: tacrolimus,ofcyclosporine
Bain P, Bajaj N, et al. Consensus Statement on the classification tremors. from the task force on tremor of the International Parkinson and Movement Disorder
Society. Mov Disord 2018;33:75-87/ Duma SR, Fung VS. Drug-induced movement disorders. Aust Prescr 2019;42:56-61/Grosset KA, Grosset DG. Prescribed
drugs and•neurological
Antibiotics: sulfamethoxazole-trimethoprim
complications. J Neurol Neurosurg Psychiatry 2004;75 Suppl 3:iii2-8.
• Parasympathetic agonists
• Steroids
• Drugs that cause parkinsonism: dopamine receptor blocking (haloperidol, metoclopramide)
• Drugs that cause cerebellar ataxia
• Drug withdrawal: benzodiazepines, SSRIs (paroxetine), alcohol, opiates
Rest tremors also, but…
• Post introduction or escalation, except valproate where tremor can appear at ther. doses/ during stable Rx
• Li & TCAs tremor can (in some) improve despite continuing therapy
Myoclonus – Chorea – Dystonia - Tics
Zhou, DJ et al. Movement disorders associated with anti-seizure medications: A
Zhou, DJ et al. Movement disorders associated with anti-seizure systematic review. Epilepsy behavior. 2022;131: 108693/ Vo ML. Commonly Used
medications: A systematic review. Epilepsy behavior. 2022;131: Drugs for Medical Illness and the Nervous System. Continuum 2020;26:716-731/
108693/ Vo ML. Commonly Used Drugs for Medical Illness and the Duma SR et al. Drug-induced movement disorders. Aust Prescr 2019;42:56-61/
Nervous System. Continuum (Minneap Minn) 2020;26:716-731/Factor Factor SA, Burkhard PR, Caroff S, et al. Recent developments in drug-induced
SA, Burkhard PR, Caroff S, et al. Recent developments in drug- movement disorders: a mixed picture. Lancet neurol 2019;18:880-890/ Lizarraga
induced movement disorders: a mixed picture. Lancet neurol KJ et al. Reversible craniocervical dystonia associated with levofloxacin. J Clin
2019;18:880-890/ Janssen S, Bloem BR, van de Warrenburg BP. The Mov Disord 2015;2:10/ Dressler D. Tardive dystonic syndrome induced by the
clinical heterogeneity of drug-induced myoclonus: an illustrated calcium-channel blocker amlodipine. J Neural Transm (Vienna) 2014;121:367-
review. J Neurol 2017;264:1559-1566/ Deik AF, Shanker VL. A case of 369/ Deik A et al. Substance of abuse and movement disorders: complex
amiodarone-associated myoclonus responsive to levetiracetam. Can interactions and comorbidities. Curr Drug Abuse Rev 2012;5:243-253/Tarsy D,
J Neurol Sci 2012;39:680-681/ Jankovic J. In Bradley’s Neurology in Simon DK. Dystonia. N Engl J Med 2006;355:818-829/ Pina MA et al. Dystonia
clinical practice induced by gabapentin. Ann Pharmacother 2005;39:380-382/ Grosset KA et al.
Prescribed drugs and neurological complications. J Neurol Neurosurg
Psychiatry 2004;75 Suppl 3:iii2-8.
Vo ML. Commonly Used Drugs for Medical Illness and the Nervous Vo ML. Commonly Used Drugs for Medical Illness and the Nervous System.
System. Continuum (Minneap Minn) 2020;26:716-731/ Factor SA, Continuum (Minneap Minn) 2020;26:716-731/Ogundele MO, Ayyash HF. Review
Burkhard PR, Caroff S, et al. Recent developments in drug-induced of the evidence for the management of co-morbid Tic disorders in children and
movement disorders: a mixed picture. Lancet neurol 2019;18:880-890/ adolescents with attention deficit hyperactivity disorder. World J Clin Pediatr
Fahn S, Jankovic J. Principles and practice of movement disorders 2018;7:36-42/ Cohen SC, Mulqueen JM, Ferracioli-Oda E, et al. Meta-Analysis:
(Churchill Livingstone) Risk of Tics Associated With Psychostimulant Use in Randomized, Placebo-
Controlled Trials. J Am Acad Child Adolesc Psychiatry 2015;54:728-736.
Dystonia: Case - Propofol/ Ondansetron
26/M: Tonsillectomy under GA with propofol & desflurane. Recd. iv ondansetron as prophylaxis for post-op
nausea. Within a few mts. developed ….see video (action tremors, dystonic trunk movements including partial opisthotonus, multifocal
myoclonus)
• Propofol:
• involuntary movements, “seizure-like”
• ?GABA, self-limited
• Ondansetron (5HT3 antagonist):
• potential for extra-pyramidal side effects
• “seizure-like”
• can be mistaken to be psychogenic
• ?↓DA
• DD:
• postanesthetic shivering
• LA reaction
• emergence delirium
Ondansetron/ Propofol toxicity
*Kumar N, Hu WT. Extrapyramidal reaction to ondansetron and propofol. Mov Disord. 2009;24(2):312-3/ Carvalho DZ et al. Propofol Frenzy: Clinical Spectrum in 3
Patients. Mayo Clin Proc. 2017;92(11):1682-7.
Pharmaceutical Related Neurotoxicity
Akathisia: Acute
• Cause: DRBAs, VMAT2-, mirtazapine
• Clinical features: Internal restlessness; often with physical

signs that may include inability to sit still or relief with
movement.
• Rx: cessation of offending drug or anticholinergics/ beta blockers/ clonidine/

benzodiazepines/ opioids/ amantadine/ mirtazapine/ clonidine/ 5HT2 antagonists (ritanserine,
diphenhydramine)
• Timing: gen within hrs- days of introduction, & that helps

differentiate it from..
• Differential:
• Tardive akathisia:
• more objective manifestations than subjective distress
• Imp as with tardive akathisia, ↓ dose of suspected
offending agent may worsen symptoms/ no change
• Pseudo akathisia: objective without subjective complaints Walters A, Hening W, Chokroverty S, Fahn S. Opioid
• Psychotic agitation responsiveness in patients with neuroleptic-induced
akathisia. Mov Disord 1986;1:119-127.
Tardive Dyskinesia
TD vs DRBA-related akathisia/ parkinsonism/ dystonia
Cessation or ↓dose of the DRBA can improve DRBA-related akathisia/ dystonia/ parkinsonism but
generally has no effect on TD or may, at least initially, exacerbate the TD (that had been masked by the
DRBA); increasing the DRBA can appear to ameliorate TD by masking its symptoms
TD vs Withdrawal-emergent dyskinesias
Withdrawal-emergent dyskinesias can occur on abrupt cessation of long-term antipsychotics Rx,

particularly in children. The dyskinesia improves on resuming the drug & the dose can then be
gradually decreased.
Tardive Dyskinesia
TD is a persistent, irreversible, hyperkinetic movement disorder

caused by exposure to DRBAs for at least a few months*
*: no “safe” minimum, can even appear after a few wks of DRBA, particularly in the
elderly. Other TD risk factors are longer duration of illness, intellectual disability,
brain damage, prior adverse reaction to a DRBA
Overprescribing antipsychotics (to NH residents with dementia in particular)

continues to be a widespread problem
• The perception of ↓ed risk of drug-induced MDs associated with 2nd generation antipsychotics has
resulted in greater, often off label use, which likely offsets their improved safety.
• Although the relative risk of tardive syndromes is less with 2nd generation antipsychotics, because
the second generations antipsychotics are more widely prescribed, the number of new cases of
tardive syndromes is increasing.
Hauser RA et al. Differentiating TD... CNS Spectr 2022;27:208-217/ Factor SA et al. Recent developments in DI movement disorders. Lancet Neurol 2019;18:880-890.
MDs Due to Dopamine Receptor Blocking Agents
Reversible Irreversible
Tardive dyskinesia
(TD/ TS)
Acute Subacute
Orofacial dyskinesias*
NMS Dystonia DIP Akathisia Dystonia**

Others: chorea,, stereotypy,
dystonia, akathisia, multiple***
*or stereotypies (> older women), **often with orofacial dyskinesias, ***also ballism, athetosis,
parkinsonism, tremor, tics, myoclonus, pain, other sensory, vocalization, mixed, Pisa syndrome
Hauser RA et al. Differentiating TD... CNS Spectr 2022;27:208-217/ Factor SA et al. Recent developments in DI movement disorders. Lancet Neurol 2019;18:880-890.
Tardive Dyskinesia: Treatment
“Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) & must be
recommended as treatment. Clonazepan and Ginko biloba probably improve TD (Level B) and should be
considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C).
Pallidal DBS possibly improves TD and might be considered as treatment for intractable TD (Level C).
There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or
switching from typical to atypical DRBA (level U).”
VMAT2 -
↓ DA storage & release
↓ overstimulation of supersensitive
striatal D2 DA receptors that cause TS
M of A: reversible high-affinity inhibitors of mono-

amine uptake into granular vesicles of presynaptic
neurons by binding selectively to VMAT-2
Note: Since a patient on a DRBA may have DIP with TD, use of a VMAT2 - may help the TD & negatively impact the parkinsonism
Bhidayasiri R et al. Updating the recommendations for Rx of TS: A systematic review of new evidence and practical treatment algorithm. J Neurol Sci 2018;389:67-75.
April 22, 2022 (Saturday)
12.15 pm – 2.15 pm
Neurologic Complications of Other Pharmaceuticals

1.25 pm – 2.00 pm
Neeraj Kumar, MD
Department of Neurology, Mayo Clinic,
Rochester, MN

Syllabus Pharmaceuticals Related Neurotoxicity C16 Kumar April 22 Sat 2023 AAN

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April 22, 2023 (Saturday)

Neurologic Complications of Other Pharmaceuticals

Off label usage: Financial Relationship(s):

Be aware of neurologic toxicities related to

Other settings for glycopyrrolate use:

Serotonin Syndrome: Case

20/F: admitted with MSΔ &? seizure. Meds:

Serotonin syndrome Course: improved

Rx: supportive, held fluoxetine & trazadone,

• MAO inhibitors: phenelzine, tranylcypromine, iproniazid, isocarboxazid, selegiline, furazolidone,

• Other anti-infectives: ritonavir

Neuroleptic malignant syndr./ DD: serotonin syndrome Course: improved

Rx: supportive, held meds, benzo., bromocriptine (10 mg

• Dopamine receptor blocking drugs

• Withdrawal of dopaminergic agents: l-dopa, dopamine agonists, tolcapone, amantadine

Parkinsonism Hyperpyrexia Syndrome

• Clinically: (fever, autonomic instability, MS changes)…. rigidity, hyporeflexia, ↑↑CPK…movement disorders

Mental Time Pupils Tone Reflexes CPK BS

24F*: Ewing sarcoma, on etoposide & ifosfamide, presented with acute

Ifosfamide encephalopathy (IE) Rx: d/c ifosfamide, iv methylene blue

• Ifosfamide: alkylating agent, isomer of cyclophosphamide, prodrug, activated to ifosfamide mustard

Methotrexate Neurotoxicity: Case

Mtx induced leukoencephalopathy

• Timing: 2-14 d after Mtx

• May reverse/ be transient

• Tacrolimus leukoencephalopathy: acute (PRES-like), delayed

BG hypodensities T2/FLAIR hyperintensity (“lentiform fork” sign)

s/p BMT, on tacrolimus EGPA, on mepolizumab (IL5-, NUCALA)

• Illicit drugs: cannabis, cocaine, MDMA, amphetamines, LSD, marijuana

• Leaders: illicit drugs, sympathomimetics

CT head, CSF: N Rx: D/C sertraline & cold remedy RCVS

Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012;11:906-917.

• Sympathomimetics: alpha and beta agonists (cerebrovascular vasoconstriction, arterial-rupture)

Stroke: Case - TNF-

R MCA M1 stenosis (arrow), ACA stenosis Vertebrobasilar: Near occlusion of P1 of L MCA

CVD due to nilotinib

1 yr prior: note progression (MRA done for episodic confusion)

Course: Metronidazole d/c ed

• Timing: wks after Rx initiation

Rx: iv acyclovir, ceftriaxone, vancomycin

CSF: WBC 11, L49%; P79, G60; MRI: N

Course: Day 4, TMX-SMX discontinued, complete resultion of symptoms at 1 week follow up

? Aseptic meningitis (drug-induced): DIAM

• Others: allopurinol, azathioprine, cytarabine, salazopyrine,

• Leaders: NSAIDs, IVIG, TMP-SMX, monoclonal Abs

Medication Overuse Headaches

• Antiretrovirals: efavirenz (non-nucleoside reverse transcriptase inhibitor), integrase strand transfer

Lee A, Wall M. UpToDate. Accessed Dec 2023

DRUG REPORTED EFFECTS

• Chemotherapy: methotrexate (sp. IT), nelarabine

Myelopathy: Case - Methotrexate

Rx: d/c Mtx, folate

T2 Labs: MTHFR polymorphism

Rx with 4 cycles of bevacizumab: 5

mg/kg once every 2 weeks

…and clinical improvement

Generally distal, axonal, > sensory, dose-dependent, partially reversible

Platinum-based Taxanes Vina alkaloids Proteosome inhibitors

Agents Cisplatin, lipoplatin Paclitaxel, docetaxel, Vincristine, vindesine, Bortezomib, carfilzomib,

Rx & Course: d/c

• AI disorders associated with minocycline: systemic/nonsystemic vasculitis, drug-induced lupus, serum

• Steroid myopathy: vs Inflammatory myopathy

Rx: IVIG, steroids, Mtx