Spectrum of neurological manifestations in dengue virus infection in Northwest India

Introduction

Dengue virus belongs to the family flaviviridae. It manifests as a spectrum of illness ranging from flu-like illness to devastating haemorrhages and shock (dengue shock syndrome). The pathogenesis involved are thrombopathy, vasculopathy and coagulopathy.

Various non-haemorrhagic cardiac and neurological manifestations have been noted. The neurological involvement in dengue virus infection is not uncommon. However, encephalitis, acute disseminated encephalomyelitis (ADEM), transverse myelitis, Guillain–Barre syndrome (GBS), myositis and stroke have been reported.^1,2

There is paucity of data regarding the neurological manifestations in dengue patients from developing countries where there is the greatest prevalence of dengue virus infection. Hence, we conducted this prospective study.

Materials and Methods

This was a prospective study conducted at the Departments of Medicine and Neurology in the Christian Medical College, Ludhiana, a tertiary teaching institution in North West India. The study was carried out during an epidemic of dengue virus infection from 1 September 2010 to 31 December 2010. The diagnosis of dengue disease was based on: epidemiological (the post-monsoon period in an endemic area); clinical picture and laboratory investigations consistent with dengue infection (fever, body ache, thrombocytopenia; positive serum immunoglobulin M [IgM], enzyme-linked immunoadsorbent assay [ELISA]; or nonstructural protein 1 [NS1] antigen). ³ All patients were screened for neurological manifestations, received a clinical examination and had provided a detailed medical history.

The laboratory tests included: complete blood profile; serial platelet counts; transaminases; dengue NS1; and dengue IgM. Creatinine phosphokinase was tested in patients with severe muscle pains. Dengue IgM was detected using Pan Bio capture ELISA (< 9 Pan Bio units was negative; 9–11 was equivocal; and >11 was positive). The sensitivity of the test was 85.4–98.9% and the specificity was 95.7–100%.

Magnetic resonance imaging (MRI) brain, electromyogram (EEG) and nerve conduction studies (NCS) were carried out when indicated. The patients were managed as per the World Health Organization guideline. ³ Patients with haemorrhagic manifestations were given platelet rich concentrates as necessary.

Results

Neurological manifestations were noted in 21 (263%) of the 799 patients who were diagnosed with dengue virus infection. There were 19 men and the mean age was 33.77 ± 13.94 years.

All the patients had a history of fever with a mean duration of 4.52 ± 2.77 days. Bleeding manifestations were noted in five patients (1 gum bleeding; 2 haematuria; 1 haematochezia; 1 upper gastrointestinal bleed). The various neurological manifestations and investigations are shown in Table 1.

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Table 1

Clinical features and investigations

	M/F	Age	Neurological symptoms/signs	Lowest platelets/mm3 (150,000–350,000)	K/mEq/L (3.5–5.5 mEq/L)	AST, IU/L (<40)	ALT, IU/L (<40U/L)	Dengue, NS1/IgM	Special investigation	Neurological diagnosis
1	M	62	Quadriparesis	71,000	2.2			Positive		Hypokalaemic quadriparesis
2	M	37	Quadriparesis	28,000	1.6					Hypokalaemic quadriparesis
3	M	50	Quadriparesis	31,000	2.9	20	32	Positive		Hypokalaemic quadriparesis
4	M	24	Quadriparesis	24,000	1.6	134	49		CPK-3287	Hypokalaemic quadriparesis
5	M	24	Quadriparesis	61,000	2.7	141	89	Positive		Hypokalaemic quadriparesis
6	M	36	Quadriparesis	45,000	2.1	194	184			Hypokalaemic quadriparesis
7	M	22	Quadriparesis	26,000	1.8			Positive		Hypokalaemic quadriparesis
8	F	50	Seizures/altered sensorium	137,000	3.4	73	76	Positive	EEG- bilateral frontoparietal epileptiform foci	Encephalopathy
9	M	15	Altered sensorium	5000	3.7	48	42		MRI- B/L basal ganglia, thalamus, cerebellar hyperintensities	Encephalopathy
10	M	57	Altered sensorium	37,000	3.7	67	62	Positive	MRI- hypoxic ischaemic encephalopathy	Encephalopathy
11	M	47	Seizures/altered sensorium	23,000		305	161	Positive	MRI- normal	Encephalopathy
12	M	28	Weakness of hands	64,000	3.6	157	96		CPK-2384	Myositis
13	M	35	Quadriparesis	70,000	3.7	48	131	Positive	CPK-269	Myositis
14	M	50	Myalgia	70,000	4.3	14,000	5485	Positive	CPK-5679	Myositis
15	M	20	Myalgia	105,000	4.5	386	207		CPK-1458	Myositis
16	M	35	Quadriparesis	73,000	3.5	229	120	Positive	NCV- Axonal neuropathy	GBS
17	M	26	Quadriparesis	22,000	3.5			Positive	NCV- Demyelinating neuropathy	GBS
18	M	32	Altered sensorium/hemiparesis	16,000	4.4	139	115		MRI- B/L haemorrhagic demyelination	ADEM
19*	M	26	Altered sensorium	18,000	3.8	185	327		MRI- multifocal demyelination intraocular, retrobulbar and optic N head hematoma with proptosis periorbital oedema	ADEM
20*	F	37	Altered sensorium	16,000	3.9	802	1902			ICB
21*	M	18	B/L foot drop	127,000	2.8	142	39	Positive	USG- hematoma right inguinal, right upper thigh and suprapubic region	Lumbar plexopathy

*

Patients had bleeding episodes

M, male; F, female; K, potassium; AST, aspartate transaminases; ALT, alanine transaminases; B/L, bilateral; CPK, creatinine phosphokinase; ICB, intracranial bleed; NCV, nerve conduction velocity; USG, ultrasonography

Discussion

Dengue infection is widespread in the tropics. The incidence of neurological manifestations in patients diagnosed with dengue haemorrhagic fever has been documented to vary from 3% in prospective dengue haemorrhagic fever studies to 25% in retrospective studies. ⁴ In our study the incidence was 2.63% (21/799). Dengue virus was earlier considered to be a non-neurotropic virus. ⁵ However, there are reports describing neurologic involvement in dengue virus infection. ⁶ Neuroinvasion has been reported in five fatal cases of dengue encephalopathy in which the dengue virus antigen was detected in the brain by immunochemistry. ⁷

Dengue fever with hypokalaemic quadriparesis has been seen in earlier studies.^8,9 The mechanism of hypokalaemia in patients with dengue fever may be due to the redistribution of potassium in cells or transient renal tubular abnormalities leading to increased urinary potassium wasting. ⁸ All seven dengue fever patients in this series made a dramatic recovery with minimal potassium supplementation compared to the hypokalaemic paralysis of other aetiologies where longer and larger potassium supplementation was needed.

Encephalitis is one of the common manifestations of dengue neurological disease. ¹⁰ Encephalopathy is attributed to: cerebral oedema; anoxia; haemorrhage; hyponatraemia; liver or kidney failure; micro capillary haemorrhage; or release of toxic substance.^1,10 Cam et al. noted 27 cases of DHF developing encephalopathy. Of these 26 were comatose, 21 had convulsions and one had hemiplegia. No abnormalities were noted on MRI in four of 18 patients with encephalopathy. Other lesions noted on MRI were oedema; scattered focal lesions; cerebral oedema; and, in one, cerebral haemorrhage. ¹¹

Myositis was present in four of our patients. Misra et al. reported five patients presenting with acute pure motor weakness with raised creatinine kinase. ¹² EMG and muscle biopsy were consistent with myositis in one of those patients. The pathogenesis of myositis may incriminate myotoxic cytokines, particularly tumour necrosis factor. ¹³

GBS and ADEM are the immunological manifestations identified in dengue fever. The proposed mechanism for GBS is an antecedent infection evokes an immune response, which in turn can affect the myelin or the axon of peripheral nerve. ¹⁴ Both the patients with GBS had recovered completely with conservative management. ADEM following dengue fever has been reported earlier. ¹⁵ In ADEM either antiviral antibodies or a cell mediated response to the pathogen may cause cross reaction with the myelin auto antigen resulting in demyelination.

Intracerebral haemorrhage has been postulated as the most common cause of coma in dengue fever patients bleeding from other sites. ¹⁶ Siriyakorn et al. reported the first case of dengue with bilateral brachial plexopathy. ¹⁷ Although plexopathy has been identified in various viral infection, it is a very rare presentation in dengue infection. One of our patients had lumbar plexopathy.

Mortality rates reported in cases of neurological dengue infection ranged from 5% to 8.35%.^1,4,9 Kamath et al. also noted that most neurological events were related to the perfusion status of subjects studied and were found to be the most common cause of death in complicated dengue infections. ⁴

Limitations of this study included the absence of serological confirmation in nine patients. Dengue IgM ELISA was done after one week of fever. We could not document the same in patients who either succumbed early to the illness or those who had been discharged. However, as these patients presented during an epidemic with the clinical presentation of dengue fever, the diagnosis was not disputed.

Conclusion

Clinicians treating dengue fever should be aware of the varied associated neurological manifestations. In this group of 21 (2.63%) patients who had neurological manifestations, lumbar plexopathy, GBS and ADEM were rare presentations of dengue infection. In patients presenting with quadriparesis, prompt differentiation between GBS and hypokalaemia are critical in management and prognostication.