Neurology departmentAcademic Half day

Emergency Lecture series

Iatrogenic neurology

Mohammed AlkuwaitiR3

Content:

• Neuroleptic Malignant Syndrome

• Serotonin syndrome

• Acute dystonic reaction

• Chemotherapy induced neuropathy

Case 1:• “Ms. A,” a 25-year-old woman with paranoid schizophrenia, presented with an

acute psychotic episode after having stopped taking her medication.

• Over a 10-hour period in the ER she received two IM injections of haloperidol (5 mg each) and required intermittent physical restraint for safety. Her prior regimen of 10 mg/day of oral haloperidol and 1 mg/day of benztropine was resumed.

• The following morning, Ms. A was noted to be diaphoretic and in moderate distress. Vitals: HR 140 bpm, Bp 145/92 mmHg, RR 26 bpm, and Temp 40.2 °C (rectal). Physical examination demonstrated generalized rigidity and tremulousness in all extremities, and her mental status was consistent with delirium.

• Laboratory studies were remarkable for a WBC of 15,000 cells/ml and a CK 45,050 IU. Elevated serum transaminases. Normal electrolytes and creatinine. Urine toxicology screen was negative.

• CSF: normal, and cultures of blood and urine were negative. A CXR was normal.

• EEG: diffuse, generalized slowing, and CT revealed no acute intracranial pathology.

Neuroleptic Malignant Syndrome

Def:– Is a life threatening neurologic emergency associated with

the use of neuroleptic agents.• Fever, Rigidity, Mental status changes, dysautonomia.

Epi:•Incidence rates

– 0.02 to 3 % PTs on neuroleptic agents – Mostly Young adults (age range 0.9 to 78 yrs)– M : F 2:1

Associated medications• Neuroleptic agents 

– Often "typical” agents (Potency High > Low)• Including chlorpromazine, fluphenazine, haloperidol, paliperidone,

perphenazine, and thioridazine.

– ”Atypical" agents (less common)• Include aripiprazole, clozapine, olanzapine, quetiapine, risperidone,

and ziprasidone.

– Antiemetic drugs (eg, domperidone, metoclopramide, promethazine, prochlorperazine)

– Usually develop during the first two weeks of neuroleptic therapy• Wider range (After a single dose to many yrs of therapy)

It is not a dose-dependent phenomenon, but higher doses are a risk factor.

Associated risk factors• Pharmacological Risks factors:

• Recent or rapid dose escalation, • Switch from one agent to another• parenteral administration, depot formulations• Concomitant use of Lithium

• Environmental– Elevated temperature has been proposed as contributing factor.

• Clinical risk factors – Over representative of certain psychiatric conditions

• e.g acute catatonia, and extreme agitation., restraints– Comorbid acute medical illness (infection, trauma, surgery)– comorbid substance abuse.– Dehydration in 92% (? Casue vs effect)

Antiparkinson medication withdrawal

•  L-Dopa or dopamine agonist therapy,• Withdrawal or reduction or switching agents

• Infection and surgery are possible precipitants as well. Unrelated to changes in treatment or altered levodopa kinetics.

• This may be considered a distinctive disorder – Neuroleptic malignant-like syndrome.– Usually milder form

Familial predisposition

The human dopamine D2 receptor gene (DRD2)• - A TaqI A restriction fragment polymorphism containing A1 and A2 alleles.

Patients with one or two A1 alleles:- Lower dopamine D2 receptor density - Diminished dopaminergic activity and glucose

metabolism in brain regions abundant with dopamine receptors.

PATHOGENESIS — – The cause of NMS is unknown. – Current theories are limited in their ability to explain all clinical

manifestations.

Main:– Dopamine receptor blockade is central to most theories.

• several lines of evidence: – Withdrawal of dopaminergic drugs can precipitate an

NMS-like syndrome; – Most drugs associated with NMS produce dopamine

receptor blockade; – The risk of NMS appears to be correlated with the

dopamine- receptor-binding affinity of drugs; – Dopaminergic drugs have been used in treatment of

NMS symptoms;

Clinical Manifestations• Typical symptoms — • The tetrad of NMS symptoms typically evolves over one to three days.

– Mental status change: 1st in 82%. “Agitated delirium with confusion”. • Catatonic signs and mutism can be prominent. • Evolution to profound encephalopathy with stupor and eventual coma is

typical.

– Muscular rigidity is generalized. "lead pipe rigidity” +/- cogwheel phenomenon. • Other motor abnormalities include “Dyskinesias” e.g tremors, dystonia,

opisthotonus, trismus.• Patients can also have prominent sialorrhea, dysarthria, and dysphagia.

– Hyperthermia is a defining symptom according to many diagnostic criteria. Temp of >38ºC is typical (87 percent), but temp, >40ºC, is common.

– Autonomic instability:• tachycardia (in 88 percent), • labile or high blood pressure (in 61 to 77 percent),• Tachypnea (in 73 percent) • Diaphoresis, often profuse.

DSM IV dx criteria

Laboratory abnormalities• Elevated serum CK — due to rigidity

– Typically >1000 IU/L, may reach >100,000 IU/L. – Normal CK can be seen if rigidity is not clearly well developed.

Other laboratory findings are non-specific• Leukocytosis: WBC typically 10,000 to 40,000/mm3. +/- left shift.• LDH & LFTs mild elevation • Electrolyte abnormalities:

– hypocalcemia, hypomagnesemia, hypo and hypernatremia, hyperkalemia, and metabolic acidosis.

• Myoglobinuric acute renal failure can result from rhabdomyolysis.

• A low serum iron concentration (mean 5.71 µmol/L; normal 11 to 32 µmol/L) is commonly seen in NMS patients and is a sensitive (92 to 100 percent) but not specific marker for NMS among acutely ill psychiatric patients

• CSF: Normal in > 95% of cases, rarely nonspecific elevation in protein• Imaging: normal• EEG: may demonstrate generalized slowing consistent with metabolic

encephalopathy.

Diagnosis of Exclusion

• Central, systemic, and toxic causes of hyperthermia and rigidity must be excluded,

• as well as other causes of rhabdomyolysis and altered mental status.

• Serotonin syndrome — usually caused by use of SSRIs and has a similar presentation to NMS. Distinguishable features:– Shivering, hyperreflexia, myoclonus, and ataxia – Nausea, vomiting, and diarrhea. – Milder rigidity and hyperthermia.

• Malignant hyperthermia — A rare genetic disorder. Occurring with use of potent halogenated inhalational anesthetic agents and succinylcholine. Distinguished features:– clinical setting – more fulminant. – NMS patients more susceptible to it.– MH is caused by a genetic defect in a sarcoplasmic reticulum calcium channel protein, which results in

excessive calcium release into skeletal muscle after exposure to triggering medications.

• Malignant catatonia — usually a behavioral prodrome of weeks that is characterized by psychosis, agitation, and catatonic excitement. Laboratory values are more typically normal. Difficult to distinguish.

• Other drug-related syndromes — – Withdrawal of intrathecal baclofen therapy has been associated with an NMS-like syndrome in several case

reports .– Acute intoxication with certain recreational drugs, especially cocaine and ecstasy (3,4-

methylenedioxymethamphetamine, MDMA), can be confused with NMS.

Treatment and Management

• Stop causative agent• Supportive care

– A B C– Rehydration

• Insensible fluid loss• Washout CK

– Correction of electrolytes + metabolic abn. (bicarb loading)

– Cooling blankets (gastric lavage, ice packs, Tylenol, ASA)– Lowering the Bp– DVT Prophylaxis

Medical treatment

Based mostly upon case reports and clinical experienceTheir efficacy is unclear:

• Benzodiazepines: ameliorate agitation – A trial of lorazepam 1 to 2 mg parenterally is a reasonable first-line

intervention for patients with acute NMS.

•Dantrolene is a skeletal muscle relaxant.– Effective in treating malignant hyperthermia + rigidity. Rapid onset– Doses of 1 to 2.5 mg/kg IV, maximum dose of 10 mg/kg/day– Associated: risk of hepatotoxicity, – 10 days then taper– Time to complete recovery was reduced to 9 days (from a mean of 15

days)

Medical treatment• Bromocriptine, a dopamine agonist, to restore dopaminergic tone.

– Doses of 2.5 mg (through NG tube) every six to eight hours are titrated up to a maximum dose of 40 mg/day.

– 10 days then taper.– Time to complete recovery was reduced to 10 days (from a mean of

15 days)

• Amantadine has dopaminergic and anticholinergic effects– Alternative to bromocriptine. – An initial dose is 100 mg PO or NG, max dose of 200 mg q12 hrs.

Electroconvulsive therapy “ECT”• NO prospective, randomized, controlled data supporting its efficacy.

• The rationale for the use of electroconvulsive therapy (ECT) in NMS includes:– its efficacy in treating malignant catatonia – and reports of Parkinsonism improving with ECT.

• ECT is generally reserved for patients not responding to other treatments.

• During ECT succinylcholine should be avoided in patients with rhabdomyolysis to prevent acute hyperkalemia and cardiovascular complications.

Prognosis• Reported recovery times are 7 to 11 days.• Mortality rates are 5 to 20%

– Predictors: severity + medical complications.

Restarting Neuroleptics– Wait atleast 2 wks – Use lower potency agents– Start with low dose + titrate slowly.– Avoid concomitant lithium– Avoid dehydration.

Serotonin SyndromeDef: Is a potentially life-threatening condition associated with increased serotonergic activity in the CNS and PNS due to adverse drug reaction.

- Therapeutic drug use- Intentional self poisoning- Interaction between drugs

Epi:- Increasing incidence in parallel the increasing use of serotonergic agents

in medical practice.

- 14 to 16 % of persons who overdose on SSRIs.

Case:18 yr F previously healthy. In January started on Phenelzine for stress by a psychiatrist after failure of Imipramine, flurazepam and diazepam. Late February had her tooth extracted so was given Percodan (ASA + Oxycodone) for pain. Few days later had Fever and Otalgia so her Family MD prescribed Erythromycin and Chlorpheniramine.

Over the next few days worsening fever 41 C, chills, myalgias and arthralgias. In ER pt was agitated, febrile, hyperemic right temporal memebrane, clear chest and petechiae on right thigh.

Labs: WBC 18000, CXR: clear.

She was started on IV fluids + Tylenol and pan-cultured. Admitted to Medical floor 02:00.

Provisional dx : Viral syndrome with hysterical symptoms.

Plan: No Abx, wait for Cx, D/C phenelzine and 25mg of meperidine be givin for agitation and shivering.

03:30 Meperidine IM givinPt more restless, confused and thrashing the bed.

04:30 Restraints + 1mg Haloperidol

Pt calm down for short period and was able to take her Tylenol by mouth.

~06:30 More agitated + Axilla temp of 42 C cooling blankets + cold compresses. Respiratory arrest and could not be resuscitated.

Seven 5-HT 1 to 7 receptors

5-HT2A Associated with the condition

Serotonergic neuronsCNS:

- Primarily in the midline raphe nuclei.

Regulation of:- Wakefulness, affective

behavior, food intake, - Thermoregulation, emesis, - Sexual behavior.- Nciception - Motor tone.

PNS:- assists in the regulation of:

- vascular tone - gastrointestinal motility.

Clinical features• Triad of

– Mental status changes,• Include anxiety, agitated delirium, restlessness, and disorientation

– Neuromuscular abnormalities• tremor, muscle rigidity, myoclonus, hyper-reflexia, and bilateral Babinski sign

– Autonomic hyperactivity,

• Include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea

Laboratory Evaluation• Nonsepsific

– Elevation of WBC– Elevation of CK– Decrease serum bicarbonate conc.

Complications: Including- Seizure- DIC- Rhabdomyolysis, Myoglobinuria, “Renal failure”- Metabolic acidosis, - ARDS

Diagnostic criteriaHunter Toxicity Criteria Decision Rules.84 % sensitive and 97 % specific

To fulfill Criteria:A patient must have taken a serotonergic agent and meet ONE of the following conditions:

•Spontaneous clonus

•Inducible clonus PLUS agitation or diaphoresis

•Ocular clonus PLUS agitation or diaphoresis

•Tremor PLUS hyperreflexia

•Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Differential diagnosis

Management

• Removal of precipitating drugs• Monitored care• Supportive care

– Monitored care, IV fluids, correction of electrolyte abn.

• Control of agitation (Chemical > physical)– Sedation with benzodiazepines IV. (prolonged survival in rats)– Butyrophenones (eg, droperidol and haloperidol) should be avoided;

due to anticholinergic properties that inhibit sweating and increase body heat.  

Management• 5-HT2A Antagonist

– Antidote: Cyproheptadine — • If benzodiazepines and supportive care fail to improve agitation and

correct vital signs,

• H1 receptor antagonist + nonspecific 5-HT1A and 5-HT2A antagonistic properties

• It also has weak anticholinergic activity.

• Control of autonomic instability– HTN and Tachycardia:

• using short acting agents. E.g esmolol or nitroprusside.– Hypotention:

• using sympathomimetic amines e.g. phenylephrine or epinephrine.

• Persistent hyperthermia– Might need elimination of muscle activity.– Sedation in moderaye case.– If temp >41.1 C paralysis, and Orotracheal intubation

• avoid succinylcholine arrhythmia due to hyperkalemia associated with rhabdomyolysis.

Prognosis• Symptoms usually resolve within 24 hours of discontinuing the

serotonergic agent and initiating care,

• PREVENTION — – Serotonin syndrome can be avoided by applying

• educating clinicians and pts on symptoms.• and modifying prescription practices

• Multi-drug regimens should be avoided, if possible.

Acute dystonic reaction“Drug induced”

Definition of Dystonia:

Dystonia is a neurologic disorder dominated by involuntary, stereotyped, patterned (sustained or spasmodic) contractions of muscles.

These movements frequently cause twisting and other abnormal movements or postures.

Lordosis or scoliosis

Tortipelvic crisis - Typically involves hip, pelvis, and abdominal wall muscles, causes difficulty with ambulation

Epidemiology:

-0.5% to 1% of patients given metoclopramide or prochlorperazine.

-Risk of reaction decreases as age increases

Etiology

The most common causes •Neuroleptics (antipsychotics),•Antiemetics•Antidepressants (esp SSRI)

•Alcohol and cocaine use increase risk.

Predisposing factors•Predisposing factors include (1) a family history of dystonia and (2) viral infection.

Etiology

Other drugs “case reports”

-Anticonvulsant drugs (carbamazepine, phenytoin), -antimalaria agents (chloroquine, hydroxychloroquine, amodiaquine)

Acute dystonic reaction

• 50% occur within 48 hrs• 90 % within 5 days of initiation of treatment.

• Risk factors:– Family hx of dystonic– Recent cocaine or alcohol use– Recent tx with potent D2 receptor anatagonist

(haldol, fluphenazine)

Pathophysiology• Drug-induced alteration of dopaminergic-cholinergic balance in

the nigrostriatum

• Mostly by dopamine D2 receptor blockade, – which leads to an excess of striatal cholinergic output. – High-potency D2 receptor antagonists are most likely to

produce an acute dystonic reaction. – Increased age may carry less risk for the development of

dystonia because of diminished numbers of D2 receptors.

Treatment:Usually Pharmacologic tx in ERAirway protection rarely required except if:

- Laryngeal or pharyngeal dystonia.

Anticholinergic agentsBenzodiazepines

Pt related risk factors for dystonia caused by tx with antipsychotic drugs.

PreventionSecondary prevention:•After the dystonia has resolved, treatment with anticholinergics should be continued in addition to the treatment with antipsychotic drugs for at least 24 to 48 hours to prevent a recurrence. •In practice, treatment with the anticholinergic drug is usually continued for four to seven days.

Neurologic Side Effect of Chemotherapeutic agents.

• Central nervous system

• Peripheral Nervous system– Generally present with stocking-glove or length-dependent

signs and symptoms.

Taxanes: microtubule stabilizing agent interferes with mitotic spindles during

cell mitosis. e.g. Paclitaxel, docetaxel, new albumin bound Paclitaxel.

usually used in Solid tumors e.g. lung, breast, and prostate cancer.

Often in combination with platinum agents.

Dose limiting toxicity, and probably single-dose toxicityas well.

• Pathogeneesis:– Possible direct effect on dorsal root ganglia sensory neurons.

Neurological complications: 10%

Clinical features:Early symptoms:

- numbness and dysesthesias that begin distally in the legs- Can be asymmetric or involve the hands or face early in the course. - Muscle stretch reflexes are diminished or absent.

Posterior column involvement:- Some patients have Lhermitte phenomenon. - impairment of proprioception and vibration sense.

Autonomic involvementDistal or proximal weakness with myalgias can occur in more severely affected patients. EMG/ NCs:

- Reduction or disappearance of sural sensory nerve potentials, - wide- spread sensorimotor axonal neuropathy in severely affected

patients.

Acute pain syndrome (some pts)- Within 1 or 2 days after treatment, - Resolves after several days. - Often involves the back and proximal limbs. - The syndrome may be caused by:

- sensitization of nociceptors

Albumin-bound paclitaxel, - Less infusional reactions with paclitaxel - Higher tumor response rate, 33% versus 19%, - Higher rate of significant neuropathy, 10% versus 2%. - The observed neuropathy is purely sensory- resolve with D/C of tx or dose reduction within an average of 3

wks

Vinca alkaloids plant-derived microtubule assembly inhibitors.

Vincristine, vinblastine and vinorelbine.

Vincristine, the oldest and most neurotoxic:

- still used in leukemias, lymphomas, myeloma, and sarcomas.

- Dose limiting toxicity

Neurological SE:

- PNS“Symmetric Sensorimotor axonal polyneurpathy”.

- Range from:

- Peripheral sensorimotor loss to Autonomic dysfunction.

- Nearly all pts to some degree with Vincristine.

- CNS (infrequent)

- Ataxia, cranial nerve palsies, cortical blindness and

- seizures (rare)

Platinum compounds Covalently bind and damage DNA e.g. Cisplatin, Carboplatin, and Oxaliplatin. Used in nearly all types of solid tumors.

PNS “Sensory neuropathy” Dose-limiting toxicity (Cumulative dose)

- Higher incidences are seen with cisplatin and oxaliplatin. - Cisplatin is more often irreversible - Mechanism: Injury/death of dorsal root ganglion neurons.

Clinical features:- Subacute length-dependent numbness, paresthesias, dysesthesias,

areflexia, and sensory ataxia. Temp sensation is relatively spared. - Dorsal columne involvement (rarely)- Worsens and spreads proximally for several months after cisplatin is discontinued

- Oxaliplatin - Induce a unique acute reversible neuropathy in addition to

CIPN. - Within hrs to days of infusion,~ 80%, distal paresthesias

and mild muscle contractions. - +/- visual changes, voice changes, perioral paresthesias- EMG in these patients shows peripheral nerve hy- perexcitability resembling neuromyoto- nia

- Triggered by Cold exposure, resolve spontaneously.- Mechanism:

- Oxalate chelate ca2+ and mg affecting calcium dependent voltage-gated Na Ch

Thalidomide is an oral immunomodulatory and anti- angiogenic agent. Uses: multiple myeloma

Neurotoxicity: CIPN

Distal sensory neuropathy in ~ 50% of patients. Rarely motor neuropathy.

Correlated with length of tx. A recent study by Mileshkin L et al, 2006:75 patients with relapsed or refractory myeloma, correlated

symptoms with length of treatmentA comparison of 6 months versus 12 months of thalidomide therapy.Resulted in CIPN in 38% and 78% of patients, respectively.

Lenalidomide, a novel analog of thalidomide, Much less neurotoxic ~ 15% or less.

Cytarabine A nucleotide analog precursor that inhibits DNA polymerase, Uses:

IV in almost all types of leukemia Intrathecal treatment of leukemia or lymphoma.

Neurotoxicity:

Irreversible cerebellar ataxia has long been associated with higher doses of cytarabine, age over 40, and abnormal liver or kidney function. If treatment is continued after onset of symptoms, neurologic deficits can be permanent.

High-dose cytarabine is occasionally associated with peripheral neuropathy Including:

- distal sensorimotor polyneuropathy;

- brachial plexopathy;

- Rapidly progressive, ascending neuropathy resembling GBS

Prevention and Treatment Agents with possible protective effects on chemotherapy-induced neuropathy includes:•acetylcarnitine, •amifostine, •glutamine, •glutathione, •vitamin E,•xaliproden, Mostly studied in preclinical animal models or small uncontrolled clinical trials.

The most extensively studied- amifostine, an organic thiophosphate with cytoprotective effects. - Use was not recommended due to conflicting results from published

randomized trials.

- Vitamin E exerted a protective effect in small randomized studies of patients receiving paclitaxel and/or cisplatin.

Nortriptyline, gabapentin, and lamotrigine seem to benefit individual patients but have not been shown to be effective in a few placebo-controlled, double- blinded studies.

References• Risk factors for neuroleptic malignant syndrome. A case-control study.Keck PE Jr,

Pope HG Jr, Cohen BM, McElroy SL, Nierenberg AA. Arch Gen Psychiatry. 1989;46(10):914.

• Progression of symptoms in neuroleptic malignant syndrome. Velamoor VR, Norman RM, Caroff SN, Mann SC, Sullivan KA, Antelo RE. J Nerv Ment Dis. 1994;182(3):168.

• Neurologic complications of chemotherapy agents , George Kannarkata, Erin E. Lasherb and David Schiffc • Neurological complication of chemotheraputic agents. AAN Continum