Beta-thalassemia major complicated by intracranial hemorrhage and critical illness polyneuropathy.

Intracranial hemorrhage (ICH) is rarely seen in patients with thalassemia. A seven-year-old male, known case of beta-thalassemia major, on irregular packed cell transfusions (elsewhere) and non-compliant with chelation therapy, presented with congestive cardiac failure (Hb-3 gm/dl). He received three packed red cell transfusions over 7 days (cumulative volume 40 cc/kg). On the 9th day, he developed projectile vomiting and two episodes of generalized tonic-clonic convulsions with altered sensorium. He had exaggerated deep tendon reflexes and extensor plantars. CT-scan of brain revealed bilateral acute frontal hematoma with diffuse subarachnoid hemorrhage (frontal and parietal). Coagulation profile was normal. CT-angiography of brain showed diffuse focal areas of reduced caliber of anterior cerebral, middle cerebral, and basilar and internal carotid arteries (likely to be a spasmodic reaction to subarachnoid hemorrhage). He required mechanical ventilation for 4 days and conservative management for the hemorrhage. However, on the 18th day, he developed one episode of generalized tonic-clonic convulsion and his sensorium deteriorated further (without any new ICH) and required repeat mechanical ventilation for 12 days. On the 28th day, he was noticed to have quadriplegia (while on a ventilator). Nerve conduction study (42nd day) revealed severe motor axonal neuropathy (suggesting critical illness polyneuropathy). He improved with physiotherapy and could sit upright and speak sentences at discharge (59th day). The child recovered completely after 3 months. It is wise not to transfuse more than 20 cc/kg of packed red cell volume during each admission and not more than once in a week (exception being congestive cardiac failure) for thalassemia patients.

Intracranial hemorrhage (ICH) is seen very infrequently in thalassemia major, and around 15 such pediatric patients have been reported in the literature.[1] In addition, critical illness polyneuropathy (CIP) develops rarely in children, around 30 cases have been reported till date.[23] We report a child of beta-thalassemia major, who was admitted to the Pediatric Intensive Care Unit (PICU) with ICH (manifesting as convulsions and altered sensorium) and CIP leading to quadriplegia.

Case details

A seven-year-old-male, Indian, first issue of a third-degree consanguineous marriage, was hailing from Buldhana district (Maharashtra, India). At the age of 3 years and 10 months, he was diagnosed in our institute as a case of beta-thalassemia major. He was not regular in his follow-ups, used to take blood transfusions irregularly, and was not compliant with his oral iron chelation therapy (deferasirox, 20 mg/kg/day). He followed up irregularly for next the 10 months and then was lost to follow-up. He had taken oral chelation therapy for 10 months from December 2014 to September 2015. Since last 20 months, he was not receiving any oral chelation therapy owing to financial constraints. There was an absence of history of hypertension, seizures, or renal ailments in the past. His developmental milestones were appropriate for age. His weight was 18 kg (3rd percentile), and his height was 117 cm (15th percentile). On admission to our institute, he had progressively increasing pallor and easy fatigability for last 15 days. On presentation, he was afebrile, had tachycardia (135 beats per min), tachypnea (33 breaths per min), BP of 100/58 mmHg in right arm in the supine position, and raised jugular venous pressure (8 cm). He had severe pallor and hemolytic facies (frontoparietal bossing, maxillary prominence, and depressed nasal bridge) with pitting pedal edema. The cardiovascular system examination revealed a soft systolic hemic murmur. An abdominal examination revealed a firm, tender hepatomegaly of 6 cm (span 8 cm) and firm splenomegaly (8 cm). The respiratory system examination revealed tachypnea with bilateral basal crepitations. The preliminary investigations on admission to our institute are presented in .

Case details (continued):

On admission, in view of severe anemia and congestive cardiac failure, he received 10 ml/kg of packed red cell transfusion with due precautions (post-transfusion Hb was 4.2 g/dl). Two more packed cell transfusions were given at 15 ml/kg on the 3rd day (post-transfusion Hb was 7 g/dl) and 7th day of hospital stay (post-transfusion Hb was 9.4 g/dl). For the evaluation of suspected hypersplenism, the child continued the hospital stay further. On the 9th day of ward stay, at 7 am, the child had two episodes of projectile vomiting followed by two episodes of generalized tonic-clonic convulsions. On examination, he had a Glasgow Coma Scale (GCS) of 8/15 with signs of raised intracranial pressure [heart rate 68 beats per min and BP of 120/80 mmHg (99th percentile) in the right upper arm in supine position]. Central nervous system examination revealed absence of papilledema, normal muscle tone, >3/5 muscle power, brisk deep tendon reflexes, and bilateral extensor plantar responses. Prompt seizure control was achieved using intravenous midazolam (0.1 mg/kg), and the patient was loaded with intravenous levetiracetam (20 mg/kg) to prevent further convulsions.

1. What could be the cause of new onset seizures in a seven-year-old child with thalassemia?

Reply: The possible causes of unprovoked seizures in a seven-year-old child with thalassemia include

Intracranial infections (e.g., tuberculoma and neurocysticercosis)

ICH (e.g., coagulopathy and vascular malformations)

Metabolic derangements (e.g., hypoglycemia, hypocalcemia, and electrolyte imbalance)

Posterior reversible encephalopathy syndrome

Cerebral infarction (due to thromboembolic phenomena)

Case details (continued):

The child required endotracheal intubation in view of poor sensorium (GCS 7/15) and was transferred to PICU. The plain computed tomographic scan (CT scan) of the brain done within 3 h of the convulsions revealed bilateral acute frontal hematoma with diffuse subarachnoid hemorrhage in bilateral frontal and parietal regions (). The CT angiography of brain done after 2 days showed bilateral narrow caliber of clinoid and supraclinoid part of internal carotid artery with irregular narrowing of the middle cerebral artery and anterior cerebral artery with areas of dilatation with similar changes in basilar artery and the cortical branches of anterior cerebral artery and middle cerebral artery, which was interpreted by the radiologist as likely to be a spasmodic reaction secondary to subarachnoid hemorrhage ().

Computerized tomography (First scan) of brain (axial section) showing bilateral acute frontal hematoma (vertical arrows) with diffuse subarachnoid hemorrhage in bilateral frontal and parietal region (horizontal arrows)

Computerized tomography (Second scan) cerebral angiography of brain (sagittal section) - bilateral narrow caliber of clinoid and supraclinoid internal carotid artery with irregular narrowing of middle cerebral artery and anterior cerebral artery (small arrow) with areas of dilatation with similar changes in basilar artery (big arrow) and the cortical branches of anterior cerebral artery and middle cerebral artery

Coronal fluid-attenuated inversion-recovery (FLAIR) magnetic resonance image (Third scan) showing multiple subacute intracerebral hemorrhages in bilateral frontal (black arrows) and subarachnoid hemorrhage. The image also shows significantly enlarged calvarium secondary to thalassemia

2. What makes thalassemia patients more vulnerable for ICH?

Reply: The precise cause of ICH in patients with thalassemia remains unknown, however, many hypotheses have been put forth to explain this catastrophic event. The details of the same are mentioned in . Our patient received multiple transfusions within a few days to build-up the Hb. The cause for the parenchymal hemorrhage (without coagulopathy) in our patient seems to be due to the inability of the blood vessel walls to handle a sudden increase in viscosity of blood after the repeated transfusions.[4] The other causes mentioned in were excluded in our patient on the basis of clinical presentation and investigations.

Case details (continued):

The child was evaluated for the etiology of ICH. The details of the same are mentioned in . In light of the clinical presentation and investigations, the most likely cause of the ICH in our patient could be weakened blood vessel wall.

3. Can ICH be avoided in thalassemia patients?

Reply: Thalassemia patients who are non-compliant and present in congestive cardiac failure (due to severe anemia) pose a therapeutic dilemma. Their CCF mandates rapid/repeated transfusions but puts them at potential risk of developing ICH. The cause of the ICH in these multiply transfused patients appears to be the recent blood transfusion/s (within past few days), especially multiple transfusions within a short interval of time. Hence, it is advisable not to transfuse more than 20 cc/kg of packed red cells in thalassemia patients in every admission and the frequency of transfusions should not be more than once in a week (with an exception of those who present in congestive cardiac failure or are critically ill).[5] Hence, it is advisable to transfuse these patients with blood that is just enough to treat the congestive cardiac failure rather than aggressively trying to correct the anemia.

Case details (continued):

Neurosurgery reference was taken and advise was to manage ICH conservatively (head-end elevation, sedation, mechanical ventilation, and hypertonic saline). During the PICU stay, his GCS improved to 13/15, electrolytes were normal, had normal urine output, and he was on IV levetiracetam (20 mg/kg in two divided doses). After 4 days of mechanical ventilation (muscle relaxants were not used) and controlling the raised intracranial pressure (dexamethasone), the patient was extubated and shifted back to the pediatric ward (on the 15th day of admission). Subsequently, on 18th day, the child had one episode of generalized tonic clonic-convulsion. Levetiracetam loading dose (20 mg/kg) was given intravenously and the maintenance dose was increased (to 30 mg/kg). The serum sodium level on the day of seizures was 124 mEq/L and potassium level was 3.9 mEq/L, hence sodium correction was initiated. The child had signs of raised intracranial pressure (heart rate 61 beats per min and BP was 114/78 mmHg). In view of poor sensorium, the child was re-intubated (muscle relaxants were not used, but dexamethasone was used for the raised intracranial pressure) and transferred again to PICU. A repeat CT brain was done in suspicion of a rebleed but did not show any new hemorrhages. On the 9th day of this second episode of PICU stay (i.e., 28th day of hospital stay), the child was noticed to have quadriplegia. The child now had normal fundus, muscle hypotonia in lower limbs with hypertonia in upper limbs, muscle power 0/5, and exaggerated deep tendon reflexes with bilateral extensor plantar responses. After a few days of supportive care, the child was extubated and transferred back to the pediatric ward (on the 36th day of hospital stay) with a plan to work-up for the possible causes of the quadriplegia.

4. What could be the cause for quadriplegia in such a patient?

Reply: The possible causes of quadriplegia in our patient include cervical cord injury that can be because of hyper-extension of neck during intubation[6] or extramedullary hematopoietic tissue in the central canal,[7] critical illness polyneuropathy and myopathy (CIPM),[8] polyneuropathy related to thalassemia,[9] Guillain-Barré syndrome (GBS),[10] bilateral precentral gyrus damage by hematoma[11], and hypokalemia.

Case details (continued):

Considering the above-mentioned hypotheses, we planned a magnetic resonance imaging of the brain with MR angiography with MR venogram with a spine study (for the possible cervical cord injury); electromyography and nerve conduction study (for polyneuropathy/GBS); and a serum creatinine phosphokinase level (for possible myopathy). Their results are summarized in .

Case details (continued):

Interpreting the investigations done, it appears that the ICH manifested as hypertonia in upper limbs, exaggerated deep tendon jerks in all 4 limbs and extensor plantar responses and CIP resulted in hypotonia in lower limbs. The final diagnosis of CIP was made based on - repeated PICU admissions, need for mechanical ventilation, and nerve conduction study suggesting polyneuropathy. Although this seems to be a clinical paradox, our patient had a central lesion due to the intracranial bleeding, which can explain the brisk deep tendon reflexes.[1213]

5. What is CIP/critical illness myopathy?

Reply: CIP and critical illness myopathy (CIM) are the complications of critical illness; manifest as flaccid, symmetrical muscle weakness involving limbs, and the respiratory muscles with relative sparing of the cranial nerves.[21415] These are frequent complications of severe illness, involving both motor and sensory axons, first described by Oslerin 1892.[15] The term “critical illness polyneuropathy” was introduced in 1984 by Bolton et al.[15] The incidence ranges from 25–45% in adults who are admitted to intensive care units and can reach up to 100% when complicated by multiple organ failure.[15] However, only one prospective study has been conducted by Banwell et al. (2003) in the pediatric age group, which has shown an incidence of 1.7%.[16] The incidence is reported to be much lesser in the pediatric age group, but more prospective studies on these entities are required for an appropriate estimate of the incidence.[3]

6. What are the factors that put thalassemia patients at risk for neuropathy?

Reply: Iron overload plays a major role in pathogenesis of the neuropathy in thalassemia and is also linked to chronic hypoxia (occurring due to anemia).[9] Polyneuropathy can be detected in 38.9%, myopathy in 27.8% of patients, and both in 16.7% patients with thalassemia.[9] Although thalassemia can cause neuropathy in adults, it is not a feature of childhood thalassemia.[17]

7. How does CIP manifest? Can it be diagnosed clinically/at bedside?

Reply: CIP manifests as weakness, muscle wasting, difficulty in weaning off from mechanical ventilator, rarely cranial nerve involvement, flaccid quadriparesis/quadriplegia, loss of deep tendon reflexes, and distal loss of sensitivity to pain, temperature, and vibration.[31415] Bedside assessment is done by using Medical Research Council scale; this score evaluates muscle power on a scale from 0 to 5 in three muscle groups of both upper and lower limbs, rendering a maximum score of 60. CIPM is diagnosed if the total score is less than 48.[14]

8. What are the additional investigations required for the diagnosis of CIPM?

Reply: Nerve conduction studies and electromyography are the mainstay investigations for diagnosis of CIPM. A significant overlap of neurophysiologic abnormalities is seen in both these conditions.

To diagnose CIM-

Creatinine phosphokinase levels -may be normal or elevated.[15]

Electromyography– will show reduction in the amplitude of compound muscle action potentials and reduced muscle fiber excitability on direct stimulation.[141518]

Muscle biopsy–may show localized or diffuse muscle necrosis and loss of type 2 muscle fibers.[19]

To diagnose CIP-

Nerve conduction study – may show normal to minimally reduced nerve conduction velocity, low-amplitude compound motor action potentials, and it will be axonal type of neuropathy.[2] Normal acceptable limits of conduction velocity (CV) is 50–60 m/s. In our patient, in the upper limbs median nerve, radial nerve, and ulnar nerve and in the lower limbs sural nerve, peroneal nerve, and tibial nerves were tested. The CV was above 50 m/s in all the nerves except right peroneal nerve (47.5 m/s) and left peroneal nerves (not recordable).

An algorithm [Figure 4] has been constructed for the diagnosis of CIM and CIP.

Figure 4

Algorithm for diagnosis of CIM and CIP. Note: *If both findings are there, then CIPM, CCF- congestive cardiac failure, CIM- critical illness myopathy, CIPM- critical illness polyneuropathy myopathy, MODS- multiorgan dysfunction syndrome, NM- neuromuscular

9. How does one manage CIPM? Can it be avoided?

Reply: CIP can be effectively managed with nutritional supplementation in combination with regular physiotherapy.[1518]

CIPM can be avoided by

Aggressive treatment of sepsis, this is the most important measure to reduce the incidence of CIPM[15]

Avoiding drugs that are known to cause CIPM (such as corticosteroids, chemotherapy agents, neuromuscular blockers, and aminoglycosides)

Prevention of pressure neuropathies by careful positioning and frequent position change[15]

Strict glycemic level control in critically ill patients[15]

Early rehabilitation in the form of early mobilization with physiotherapy is an important way to prevent as well as treat CIPM[15]

Electrical muscle stimulation is helpful in immobilized patients.[15]

Case details (continued):

During the ward stay, the child received regular physiotherapy and nutritional supplements [Riboflavin (10 mg/day), Thiamine (10 mg/day), Carnitine (50 mg/kg/day), Creatine (100 mg/kg/day), Coenzyme Q (10 mg/kg/day), Methylcobalamin (100 mcg/day), Vitamin C (500 mg/day), and Vitamin E (400 IU/day)]. Although such nutritional supplements do not have any hard evidence in improving CIP, they probably are not harmful and may be empirically tried (in a hope of recovery). The child gradually showed improvement over a period of 2 weeks, in the form of started verbalizing, accepting feeds orally, with improvement in the muscle tone and power. At the time of discharge (59 days after the initial admission), the child could sit upright and converse well. Parents were counseled for the need to ensure regular blood transfusion and oral iron chelation therapy. At clinical follow-up after 3 months, the child could walk without support and had no residual neurological deficits. Presently, his cognition (attention, memory, speech, and language) are normal, however, he is not attending school. He will join school from forthcoming academic year in June 2019.

Contribution of each author

SS, MST, and SK were involved in the conceptualization of the manuscript, collecting patient data, conducting literature search, and drafting the manuscript. MNM and PP supervised the data collection, helped in literature search, and revised the manuscript for the scientific content. All the authors were involved in the clinical management of the patient. SK will act as the guarantor for the paper.

Declaration of patient consent

The authors certify that appropriate patient consent was obtained.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 1

Investigations at admission

Investigation	Results	Age appropriate reference range
Hb	3.0 g/dl	(11.5-14.5 g/dl)
Leukocyte count	3.6×103 cells/mm3	4.0-12.0×103 cells/mm3
Platelet count	280×103/mm3	120-500×103/mm3
Peripheral smear	Microcytic hypochromic red blood cells with few macrocytes, tear drop cells, and pencil cells, negative for malarial parasites
Serum electrolytes (Na+/K+)	132/4.7 mmol/L	134-143/3.3-4.6 mmol/L
BUN/serum creatinine	7.6/0.5 mg/dL	5-18/0.22-0.59 mg/dL
Serum total protein/albumin	7/4 g/dL	6.1-7.9/3.5-5.6 g/dL
Total/direct bilirubin	1.8/0.6 mg/dL	0-2.0/0-0.2 mg/dL
AST/ALT	105/99 U/L	15-50/5-45 U/L
Serum ferritin	2497 ng/mL	10-60 ng/mL
Serum LDH	3040.9 U/L	150-500 U/L
HIV ELISA test	Non-reactive	-
HBsAg/HCV	Negative	-
Direct Coombs test	Negative	-

Table 2

Possible causes for ICH in patients with thalassemia

Hypotheses
Coagulation defects (Quantitative or qualitative defect/s in platelets, deranged prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (aPTT), and factor XIII defects).[45]
Inability of blood vessel walls (weakened by chronic exposure to low viscosity blood) to handle a sudden increase in viscosity of blood after transfusion can lead to hemorrhagic stroke.[5]
Presence of circulating coagulation inhibitor (prothrombinase inhibitor) could predispose patients to cerebral hemorrhage in the face of expanded cerebral blood volumes (even at normal blood pressures).[5]
Long-standing anemia is known to increase endogenous overproduction of endothelin-1 (a potent vasoconstrictor) causing hypertension.[1]
Sudden change in the hematocrit levels after a packed red cell transfusion alter the rheological state of the blood and affects the renal perfusion, hence leads to activation of the renin-angiotensin system thus causing hypertension.[1]
Iron overload is associated with cardiomyopathy in thalassemia patients, which can be associated with stroke.[5]
Reversible cerebral vasoconstriction syndrome (RCVS) can cause cerebral vasoconstriction as well as ICH and seizures.

Table 3

Work-up for the cause of ICH

Investigations	Results
Platelet counts	Normal (260×103/mm3)
Platelet function studies (aggregation with ADP, ristocetin, collagen, and arachidonic acid)	Normal
Coagulation profile (PT/INR/aPTT)	Normal (13/0.9/32)
Factor XIII levels	Normal (82%)
ECG and 2D-echo/color Doppler study of the heart	Normal

Table 4

Results of investigations done for quadriplegia in our patient

Investigations	Results	Interpretation
MRI brain, MR angiography and MR venogram with spine study	Multiple subacute intracerebral hemorrhages in bilateral frontoparietal and subarachnoid hemorrhage without surrounding edema; as compared to previous computed tomography no new lesions were noted (Figure 3- Third scan).	No vascular malformations
	Normal MR angiography (spasmodic vascular response, which was there in the previous CT cerebral angiography, had resolved) and normal MR venogram.	No arteriovenous malformations
	Normal spine MRI study.	Rules out spine injuries, extra medullary hematopoetic tissue in the central canal and GBS
Nerve conduction study (NCS)	Severe motor axonal polyneuropathy of upper and lower limb (lower limbs more affected than the upper limbs)	Polyneuropathy
Creatinine phosphokinase (CPK)	26.2 U/L (5-130U/L)	No myopathy
Serum potassium levels	4.1 mEq/L	No hypokalemic quadriparesis